U.S. patent application number 12/739040 was filed with the patent office on 2010-11-25 for (1,4-diaza-bicyclo[3.2.2]non-6-en-4-yl)-heterocyclyl-methanone ligands for nicotinic acetylcholine receptors, useful for the treatment of disease.
This patent application is currently assigned to MEMORY PHARMACEUTICALS CORPORATION. Invention is credited to Guangxiu Dai, Brian Herbert, Richard Schumacher, Wenge Xie.
Application Number | 20100298306 12/739040 |
Document ID | / |
Family ID | 40580357 |
Filed Date | 2010-11-25 |
United States Patent
Application |
20100298306 |
Kind Code |
A1 |
Herbert; Brian ; et
al. |
November 25, 2010 |
(1,4-Diaza-bicyclo[3.2.2]non-6-en-4-yl)-heterocyclyl-methanone
Ligands for Nicotinic Acetylcholine Receptors, Useful for the
Treatment of Disease
Abstract
The present invention relates generally to the field of ligands
for nicotinic acetylcholine receptors (nACh receptors), activation
of nACh receptors, and the treatment of disease conditions
associated with defective or malfunctioning nicotinic acetylcholine
receptors, especially of the brain. Further, this invention relates
to novel compounds, which act as ligands for the .alpha.7 nACh
receptor subtype, methods of preparing such compounds, compositions
containing such compounds, and methods of use thereof. The novel
compounds include compounds of formula I: ##STR00001## wherein X,
R.sup.1, and R.sup.2 are as herein defined.
Inventors: |
Herbert; Brian; (Stockholm,
NJ) ; Schumacher; Richard; (Monroe, NY) ; Dai;
Guangxiu; (Baton Rouge, LA) ; Xie; Wenge;
(Mahwah, NJ) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD., SUITE 1400
ARLINGTON
VA
22201
US
|
Assignee: |
MEMORY PHARMACEUTICALS
CORPORATION
Montvale
NJ
|
Family ID: |
40580357 |
Appl. No.: |
12/739040 |
Filed: |
October 22, 2008 |
PCT Filed: |
October 22, 2008 |
PCT NO: |
PCT/US2008/080743 |
371 Date: |
August 17, 2010 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60981643 |
Oct 22, 2007 |
|
|
|
61050366 |
May 5, 2008 |
|
|
|
Current U.S.
Class: |
514/221 ;
540/556 |
Current CPC
Class: |
A61P 39/02 20180101;
A61P 25/14 20180101; A61P 25/22 20180101; A61P 25/30 20180101; A61P
9/10 20180101; A61P 25/00 20180101; A61P 9/00 20180101; A61P 29/00
20180101; A61P 3/10 20180101; A61P 25/24 20180101; A61P 25/16
20180101; A61P 25/32 20180101; A61P 35/00 20180101; A61P 25/34
20180101; A61P 25/18 20180101; A61P 21/00 20180101; A61P 19/02
20180101; C07D 519/00 20130101; A61P 31/18 20180101; A61P 43/00
20180101; A61P 1/04 20180101; A61P 37/06 20180101; A61P 3/04
20180101; A61P 25/28 20180101; C07D 471/08 20130101; A61P 31/04
20180101; A61P 25/20 20180101 |
Class at
Publication: |
514/221 ;
540/556 |
International
Class: |
A61K 31/551 20060101
A61K031/551; C07D 471/08 20060101 C07D471/08; A61P 29/00 20060101
A61P029/00; A61P 25/30 20060101 A61P025/30; A61P 3/04 20060101
A61P003/04; A61P 3/10 20060101 A61P003/10; A61P 25/32 20060101
A61P025/32; A61P 35/00 20060101 A61P035/00; A61P 25/28 20060101
A61P025/28; A61P 25/18 20060101 A61P025/18; A61P 25/22 20060101
A61P025/22; A61P 25/24 20060101 A61P025/24; A61P 25/16 20060101
A61P025/16; A61P 25/00 20060101 A61P025/00 |
Claims
1. A compound according to of Formula (I): ##STR00104## wherein X
is NH, N(CH.sub.3), S or O; R.sup.1 and R.sup.2 are each,
independently, hydrogen, C.sub.1-C.sub.6-alkyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.2-C.sub.6-alkenyl which is unsubstituted or substituted one
or more times by R.sup.10, C.sub.2-C.sub.6-alkynyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.3-C.sub.6-cycloalkyl which is unsubstituted or substituted
one or more times by R.sup.11, C.sub.3-C.sub.8-cycloalkenyl which
is unsubstituted or substituted one or more times by R.sup.11,
halo, OR.sup.3, SR.sup.3, NR.sup.3R.sup.4, aryl which is
unsubstituted or substituted one or more times by R.sup.12,
heterocyclyl which is unsubstituted or substituted one or more
times by R.sup.12, S(O).sub.pR.sup.13, S(O).sub.pNR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4, NO.sub.2, or
CN, or R.sup.1 and R.sup.2 taken together are ##STR00105##
--(CH.sub.2).sub.2CR.sup.9.dbd.CR.sup.9--, or --(CH.sub.2).sub.m;
R.sup.3 and R.sup.4 are each, independently, hydrogen,
C.sub.1-C.sub.6-alkyl which is unsubstituted or substituted one or
more times by R.sup.10, C.sub.3-C.sub.6-alkenyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.3-C.sub.6-alkynyl which is unsubstituted or substituted one
or more times by R.sup.10, C.sub.3-C.sub.6-cycloalkyl which is
unsubstituted or substituted one or more times by R.sup.11,
C.sub.3-C.sub.8-cycloalkenyl which is unsubstituted or substituted
one or more times by R.sup.11, aryl which is unsubstituted or
substituted one or more times by R.sup.12, heterocyclyl which is
unsubstituted or substituted one or more times by R.sup.12,
--C(O)R.sup.5, --C(O)OR.sup.5, or --C(O)NR.sup.5R.sup.6; W.sup.1,
W.sup.2, W.sup.3 and W.sup.4 are each, independently, CR.sup.7 or
N, wherein no more than one of W.sup.1, W.sup.2, W.sup.3 and
W.sup.4 is N; V.sup.1 and V.sup.2 are each, independently, O,
CR.sup.8R.sup.8, S, NH, or NR.sup.3, provided that when one of
V.sup.1 or V.sup.2 represent O, S, NH, or NR.sup.3, the other is
CR.sup.8R.sup.8; m is 3, 4, 5, or 6; n is 0, 1 or 2; p is 1 or 2;
R.sup.5 and R.sup.6 are each, independently, hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.8-cycloalkenyl, aryl, or heterocyclyl; R.sup.7 is
hydrogen, C.sub.1-C.sub.6-alkyl which is unsubstituted or
substituted one or more times by R.sup.10, C.sub.2-C.sub.6-alkenyl
which is unsubstituted or substituted one or more times by
R.sup.10, C.sub.2-C.sub.6-alkynyl which is unsubstituted or
substituted one or more times by R.sup.10,
C.sub.3-C.sub.6-cycloalkyl which is unsubstituted or substituted
one or more times by R.sup.11, C.sub.3-C.sub.8-cycloalkenyl which
is unsubstituted or substituted one or more times by R.sup.11,
halo, OR.sup.3, SR.sup.3, NR.sup.3R.sup.4, aryl which is
unsubstituted or substituted one or more times by R.sup.12,
heterocyclyl which is unsubstituted or substituted one or more
times by R.sup.12, S(O).sub.pR.sup.13, S(O).sub.pNR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4, --NO.sub.2,
or CN; R.sup.8 is, in each case independently, H,
C.sub.1-C.sub.6-alkyl which is unsubstituted or substituted one or
more times by C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy,
OH, halo or NR.sup.3R.sup.4, O--C.sub.1-C.sub.6-alkyl, OH, halo, or
NR.sup.3R.sup.4, or two R.sup.8 together may represent oxo; R.sup.9
is, in each case independently, hydrogen, C.sub.1-C.sub.6-alkyl
which is unsubstituted or substituted one or more times by
R.sup.10, C.sub.2-C.sub.6-alkenyl which is unsubstituted or
substituted one or more times by R.sup.10, C.sub.2-C.sub.6-alkynyl
which is unsubstituted or substituted one or more times by
R.sup.10, C.sub.3-C.sub.6-cycloalkyl which is unsubstituted or
substituted one or more times by R.sup.11,
C.sub.3-C.sub.8-cycloalkeny which is unsubstituted or substituted
one or more times by R.sup.11I, aryl which is unsubstituted or
substituted one or more times by R.sup.12, or heterocyclyl which is
unsubstituted or substituted one or more times by R.sup.12;
R.sup.10 is, in each case independently, halogen,
C.sub.2-C.sub.7-alkoxycarbonyl, hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-alkynyloxy, nitro, amino, C.sub.1-6-alkylamino,
dialkylamino wherein each alkyl group has independently 1 to 6
carbon atoms, aminocarbonyl, C.sub.1-6-alkyl-aminocarbonyl,
dialkylaminocarbonyl wherein each alkyl group has independently 1
to 6 carbon atoms, hydroxyalkyl having 1 to 6 carbon atoms,
hydroxyalkoxy having 1 to 6 carbon atoms, carboxy, cyano, formyl,
alkanoyl having 2 to 7 carbon atoms, benzoyl,
C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-alkylsulfamoyl,
phenoxy, formyloxy, alkanoyloxy having 2 to 7 carbon atoms, and
benzoyloxy; R.sup.11 is, in each case independently, halogen,
C.sub.1-C.sub.6-alkyl, halogenated C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkynyl,
C.sub.2-C.sub.7-alkoxycarbonyl, hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-alkynyloxy, nitro, methylenedioxy, ethylenedioxy,
amino, C.sub.1-6-alkylamino, dialkylamino wherein each alkyl group
has independently 1 to 6 carbon atoms, aminocarbonyl,
C.sub.1-6-alkyl-aminocarbonyl, dialkylaminocarbonyl wherein each
alkyl group has independently 1 to 6 carbon atoms, hydroxyalkyl
having 1 to 6 carbon atoms, hydroxyalkoxy having 1 to 6 carbon
atoms, carboxy, cyano, formyl, alkanoyl having 2 to 7 carbon atoms,
benzoyl, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-alkylsulfamoyl,
phenoxy, formyloxy, alkanoyloxy having 2 to 7 carbon atoms, and
benzoyloxy; R.sup.12 is, in each case independently, halogen,
C.sub.1-C.sub.6-alkyl, halogenated C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.5-C.sub.8-cycloalkenyl,
C.sub.2-C.sub.7-alkoxycarbonyl, hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-alkynyloxy, nitro, methylenedioxy, ethylenedioxy,
amino, C.sub.1-6-alkylamino, dialkylamino wherein each alkyl group
has independently 1 to 6 carbon atoms, aminocarbonyl,
C.sub.1-6-alkyl-aminocarbonyl, dialkylaminocarbonyl wherein each
alkyl group has independently 1 to 6 carbon atoms, hydroxyalkyl
having 1 to 6 carbon atoms, hydroxyalkoxy having 1 to 6 carbon
atoms, carboxy, cyano, formyl, alkanoyl having 2 to 7 carbon atoms,
benzoyl, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-alkylsulfamoyl,
phenoxy, formyloxy, alkanoyloxy having 2 to 7 carbon atoms, and
benzoyloxy; and R.sup.13 is in each case independently,
C.sub.1-C.sub.6-alkyl which is unsubstituted or substituted one or
more times by R.sup.10, C.sub.3-C.sub.6-alkenyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.3-C.sub.6-alkynyl which is unsubstituted or substituted one
or more times by R.sup.10, C.sub.3-C.sub.6-cycloalkyl which is
unsubstituted or substituted one or more times by R.sup.11,
C.sub.3-C.sub.8-cycloalkenyl which is unsubstituted or substituted
one or more times by R.sup.11, aryl which is unsubstituted or
substituted one or more times by R.sup.12, heterocyclyl which is
unsubstituted or substituted one or more times by R.sup.12,
--C(O)R.sup.5, --C(O)OR.sup.5, or --C(O)NR.sup.5R.sup.6; or a
tautomer thereof, or a pharmaceutically acceptable salt, ester, or
salt of an ester thereof, and wherein if the compound exhibits
chirality it can be in the form of a mixture of enantiomers or a
mixture of diastereomers, or can be in the form of a single
enantiomer or a single diastereomer.
2. A compound according to claim 1, wherein: R.sup.1 and R.sup.2
are each, independently, hydrogen, C.sub.1-C.sub.6-alkyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.2-C.sub.6-alkenyl which is unsubstituted or substituted one
or more times by R.sup.10, C.sub.2-C.sub.6-alkynyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.3-C.sub.6-cycloalkyl which is unsubstituted or substituted
one or more times by R.sup.10, C.sub.3-C.sub.8-cycloalkenyl which
is unsubstituted or substituted one or more times by R.sup.10,
halo, OR.sup.3, SR.sup.3, NR.sup.3R.sup.4, aryl which is
unsubstituted or substituted one or more times by R.sup.11,
heterocyclyl which is unsubstituted or substituted one or more
times by R.sup.11, S(O).sub.pR.sup.13, S(O).sub.pNR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4, NO.sub.2, or
CN, or R.sup.1 and R.sup.2 taken together, are ##STR00106## or
--(CH.sub.2).sub.m--.
3. A compound according to claim 1, wherein: X is NH, N(CH.sub.3),
S or O; R.sup.1 and R.sup.2 are each, independently, hydrogen,
C.sub.1-C.sub.6-alkyl which is unsubstituted or substituted one or
more times by R.sup.10, C.sub.3-C.sub.6-cycloalkyl which is
unsubstituted or substituted one or more times by R.sup.10, halo,
NH.sub.2, phenyl which is unsubstituted or substituted one or more
times by R.sup.11, naphthyl which is unsubstituted or substituted
one or more times by R.sup.11, 1,4-benzodioxan-6-yl which is
unsubstituted or substituted one or more times by R.sup.11, pyridyl
which is unsubstituted or substituted one or more times by
R.sup.11, thienyl which is unsubstituted or substituted one or more
times by R.sup.11, or NO.sub.2, or R.sup.1 and R.sup.2 taken
together, are ##STR00107## or, --(CH.sub.2).sub.m; and m is 3, 4,
5, or 6.
4. A compound according to claim 1, wherein: R.sup.1 and R.sup.2
are each, independently, hydrogen, C.sub.1-C.sub.6-alkyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.3-C.sub.6-cycloalkyl which is unsubstituted or substituted
one or more times by R.sup.10, halo, NH.sub.2, phenyl which is
unsubstituted or substituted one or more times by R.sup.11,
naphthyl which is unsubstituted or substituted one or more times by
R.sup.11, 1,4-benzodioxan-6-yl which is unsubstituted or
substituted one or more times by R.sup.11, pyridyl which is
unsubstituted or substituted one or more times by R.sup.11, thienyl
which is unsubstituted or substituted one or more times by
R.sup.11, or NO.sub.2, or R.sup.1 and R.sup.2 taken together, are
##STR00108## or, --(CH.sub.2).sub.m.
5. A compound according to claim 1, wherein R.sup.1 and R.sup.2 are
each independently H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl,
carbamoyl (NH.sub.2--CO--), phenyl, methylphenyl, ethylphenyl,
methoxyphenyl, ethoxyphenyl, fluorophenyl, chlorophenyl,
aminophenyl, cyanophenyl, nitrophenyl, naphthyl, pyridyl,
methylpyridyl, ethylpyridyl, methoxypyridyl, ethoxypyridyl,
fluoropyridyl, chloropyridyl, aminopyridyl, cyanopyridyl,
nitropyridyl, thienyl, methylthienyl, fluorothienyl, chlorothienyl,
pyazole, or methylpyrazole.
6. A compound according to claim 1, wherein R.sup.1 is H, F, Cl,
Br, cyano, methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, nitro,
amino, methylamino, ethylamino, dimethylamino, diethylamino,
cyclopropyl, cyclopentyl, cyclohexyl, acetyl, propionyl, acetoxy,
methoxycarbonyl, ethoxycarbonyl, or carbamoyl (NH.sub.2--CO--),
and/or R.sup.2 is H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl,
carbamoyl (NH.sub.2--CO--), phenyl, methylphenyl, ethylphenyl,
methoxyphenyl, ethoxyphenyl, fluorophenyl, chlorophenyl,
aminophenyl, cyanophenyl, nitrophenyl, naphthyl, pyridyl,
methylpyridyl, ethylpyridyl, methoxypyridyl, ethoxypyridyl,
fluoropyridyl, chloropyridyl, aminopyridyl, cyanopyridyl,
nitropyridyl, thienyl, methylthienyl, fluorothienyl, chlorothienyl,
pyazole, or methylpyrazole.
7. A compound according to claim 1, wherein R.sup.1 is H, F, Cl,
Br, cyano, methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, nitro,
amino, methylamino, ethylamino, dimethylamino, diethylamino,
cyclopropyl, cyclopentyl, cyclohexyl, acetyl, propionyl, acetoxy,
methoxycarbonyl, ethoxycarbonyl, or carbamoyl (NH.sub.2--CO--),
and/or R.sup.2 is phenyl, methylphenyl, ethylphenyl, methoxyphenyl,
ethoxyphenyl, fluorophenyl, chlorophenyl, aminophenyl, cyanophenyl,
nitrophenyl, naphthyl, pyridyl, methylpyridyl, ethylpyridyl,
methoxypyridyl, ethoxypyridyl, fluoropyridyl, chloropyridyl,
aminopyridyl, cyanopyridyl, nitropyridyl, thienyl, methylthienyl,
fluorothienyl, chlorothienyl, pyazole, or methylpyrazole.
8. A compound according to claim 1, wherein R.sup.1 and R.sup.2
together are --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
--(CH.sub.2).sub.5--, or --(CH.sub.2).sub.6--.
9. A compound according to claim 8, wherein R.sup.1 and R.sup.2
together are --(CH.sub.2).sub.3-- or --(CH.sub.2).sub.6--.
10. A compound according to claim 1, wherein R.sup.1 and R.sup.2
together are ##STR00109##
11. A compound according to claim 1, wherein X is NH, S or O.
12. A compound according to claim 11, wherein X is O.
13. A compound according to claim 1, wherein said compound is of
Formula Ia: ##STR00110##
14. A compound according to claim 13, wherein R.sup.1 and R.sup.2
are each independently H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl,
carbamoyl (NH.sub.2--CO--), phenyl, methylphenyl, ethylphenyl,
methoxyphenyl, ethoxyphenyl, fluorophenyl, chlorophenyl,
aminophenyl, cyanophenyl, nitrophenyl, naphthyl, pyridyl,
methylpyridyl, ethylpyridyl, methoxypyridyl, ethoxypyridyl,
fluoropyridyl, chloropyridyl, aminopyridyl, cyanopyridyl,
nitropyridyl, thienyl, methylthienyl, fluorothienyl, chlorothienyl,
pyazole, or methylpyrazole.
15. A compound according to claim 13, wherein R.sup.1 is H, F, Cl,
Br, cyano, methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, nitro,
amino, methylamino, ethylamino, dimethylamino, diethylamino,
cyclopropyl, cyclopentyl, cyclohexyl, acetyl, propionyl, acetoxy,
methoxycarbonyl, ethoxycarbonyl, or carbamoyl (NH.sub.2--CO--),
and/or R.sup.2 is H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl,
carbamoyl (NH.sub.2--CO--), phenyl, methylphenyl, ethylphenyl,
methoxyphenyl, ethoxyphenyl, fluorophenyl, chlorophenyl,
aminophenyl, cyanophenyl, nitrophenyl, naphthyl, pyridyl,
methylpyridyl, ethylpyridyl, methoxypyridyl, ethoxypyridyl,
fluoropyridyl, chloropyridyl, aminopyridyl, cyanopyridyl,
nitropyridyl, thienyl, methylthienyl, fluorothienyl, chlorothienyl,
pyazole, or methylpyrazole.
16. A compound according to claim 13, wherein R.sup.1 is H, F, Cl,
Br, cyano, methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, nitro,
amino, methylamino, ethylamino, dimethylamino, diethylamino,
cyclopropyl, cyclopentyl, cyclohexyl, acetyl, propionyl, acetoxy,
methoxycarbonyl, ethoxycarbonyl, and carbamoyl (NH.sub.2--CO--),
and/or R.sup.2 is phenyl, methylphenyl, ethylphenyl, methoxyphenyl,
ethoxyphenyl, fluorophenyl, chlorophenyl, aminophenyl, cyanophenyl,
nitrophenyl, naphthyl, pyridyl, methylpyridyl, ethylpyridyl,
methoxypyridyl, ethoxypyridyl, fluoropyridyl, chloropyridyl,
aminopyridyl, cyanopyridyl, nitropyridyl, thienyl, methylthienyl,
fluorothienyl, chlorothienyl, pyazole, or methylpyrazole.
17. A compound according to claim 13, wherein R.sup.1 and R.sup.2
together are --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
--(CH.sub.2).sub.5--, or --(CH.sub.2).sub.6--.
18. A compound according to claim 17, wherein R.sup.1 and R.sup.2
together are --(CH.sub.2).sub.3-- or --(CH.sub.2).sub.6--.
19. A compound according to claim 1, wherein said compound is of
Formula Ib: ##STR00111##
20. A compound according to claim 19, wherein R.sup.1 and R.sup.2
are each independently H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl,
carbamoyl (NH.sub.2--CO--), phenyl, methylphenyl, ethylphenyl,
methoxyphenyl, ethoxyphenyl, fluorophenyl, chlorophenyl,
aminophenyl, cyanophenyl, or nitrophenyl.
21. A compound according to claim 1, wherein said compound is of
Formula Ic: ##STR00112##
22. A compound according to claim 21, wherein R.sup.1 and R.sup.2
are each independently H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl,
carbamoyl (NH.sub.2--CO--), phenyl, methylphenyl, ethylphenyl,
methoxyphenyl, ethoxyphenyl, fluorophenyl, chlorophenyl,
aminophenyl, cyanophenyl, or nitrophenyl.
23. A compound according to claim 1, wherein said compound is of
Formula Id: ##STR00113##
24. A compound according to claim 23, wherein R.sup.7 is in each
case independently H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl,
carbamoyl (NH.sub.2--CO--), or methoxypyrrolidinyl.
25. A compound according to claim 23, wherein there is only one
R.sup.7 group and said one R.sup.7 group is H, F, Cl, Br, cyano,
methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, nitro, amino,
methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl,
cyclopentyl, cyclohexyl, acetyl, propionyl, acetoxy,
methoxycarbonyl, ethoxycarbonyl, or carbamoyl (NH.sub.2--CO--).
26. A compound according to claim 23, wherein R.sup.7 is in each
case independently H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
27. A compound according to claim 1, wherein said compound is of
Formula Ie: ##STR00114##
28. A compound according to claim 27, wherein R.sup.7 is in each
case independently H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
29. A compound according to claim 27, wherein R.sup.7 is in each
case independently H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
30. A compound according to claim 1, wherein said compound is of
Formula If: ##STR00115##
31. A compound according to claim 30, wherein R.sup.7 is in each
case independently H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
35. A compound according to claim 30, wherein R.sup.7 is in each
case independently H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
36. A compound according to claim 1, wherein said compound is of
Formula Ig: ##STR00116##
37. A compound according to claim 36, wherein R.sup.7 is in each
case independently H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
38. A compound according to claim 37, wherein R.sup.7 is in each
case independently H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
39. A compound according to claim 1, wherein said compound is of
Formula Ih: ##STR00117##
40. A compound according to claim 39, wherein R.sup.9 is in each
case independently H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
41. A compound according to claim 39, wherein R.sup.9 is in each
case independently H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
42. A compound according to claim 1, wherein said compound is
selected from:
4-[(4-Chloro-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e,
4-[(4-nitro-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
4-[(5-Methyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
4-(1H-pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane,
4-{[5-(4-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]-
nonane,
4-[(5-Phenylisoxazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
4-{[5-(2-thienyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonane-
,
4-[(5-Phenyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
4-[(5-Cyclopropyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane-
,
4-{[5-(3-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2-
]nonane,
4-(1,4,5,6-Tetrahydrocyclopenta[c]pyrazol-3-ylcarbonyl)-1,4-diaza-
bicyclo[3.2.2]nonane,
4-{[5-(2-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]-
nonane,
4-[(4-Bromo-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e, 3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)isothiazol-4-amine,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4,3-c]pyr-
azole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5,6,7,8,9-hexahydro-1-
H-cycloocta[c]pyrazole,
4-{[5-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-yl]carbonyl}-1,4-di-
azabicyclo[3.2.2]nonane,
4-{[5-(2-Naphthyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonan-
e,
4-{[5-(3-Thienyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nona-
ne,
4-{[5-(4-Fluorophenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.-
2]nonane,
4-[(5-Pyridin-2-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.-
2.2]nonane,
4-[(5-Pyridin-4-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e,
4-[(5-Pyridin-3-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]non-
ane,
5'-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1-methyl-1H,2'H-3,3'-bip-
yrazole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,4-dihydro-
chromeno[4,3-c]pyrazole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-8-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(4-fluorophenyl)-4,5-dihydr-
o-1H-indazole
4-(Isothiazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane
4-[(5-Bromoisothiazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5-dihydro-1H-benzo[g]indazo-
le
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,5-dihydroisochromeno[4,3--
c]pyrazole
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5-dihydro-1H-pyra-
zolo[3,4-f]quinoline
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-[(3S)-3-methoxypyrrolidin-1-
-yl]-1,4-dihydrochromeno[4,3-c]pyrazole
7-Bromo-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4-
,3-c]pyrazole,
3-(1,4-Dzabicyclo[3.2.2]non-4-ylcarbonyl)-1H-pyrazol-5-amine, and
tautomers thereof, and pharmaceutically acceptable salts thereof,
and wherein if the compound exhibits chirality said compound can be
in the form of a mixture of enantiomers or a mixture of
diastereomers, or said compound can be in the form of a single
enantiomer or a single diastereomer.
43. A compound according to claim 42, wherein said compound is
selected from:
4-[(4-Chloro-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e,
4-[(4-nitro-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
4-[(5-Methyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
4-(1H-pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane,
4-{[5-(4-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]-
nonane,
4-[(5-Phenylisoxazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
4-{[5-(2-thienyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonane-
,
4-[(5-Phenyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
4-[(5-Cyclopropyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane-
,
4-{[5-(3-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2-
]nonane,
4-(1,4,5,6-Tetrahydrocyclopenta[c]pyrazol-3-ylcarbonyl)-1,4-diaza-
bicyclo[3.2.2]nonane,
4-{[5-(2-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]-
nonane,
4-[(4-Bromo-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e, 3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)isothiazol-4-amine,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4,3-c]pyr-
azole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5,6,7,8,9-hexahydro-1-
H-cycloocta[c]pyrazole,
4-{[5-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-yl]carbonyl}-1,4-di-
azabicyclo[3.2.2]nonane,
4-{[5-(2-Naphthyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonan-
e,
4-{[5-(3-Thienyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nona-
ne,
4-{[5-(4-Fluorophenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.-
2]nonane,
4-[(5-Pyridin-2-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.-
2.2]nonane,
4-[(5-Pyridin-4-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e,
4-[(5-Pyridin-3-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]non-
ane,
5'-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1-methyl-1H,2'H-3,3'-bip-
yrazole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,4-dihydro-
chromeno[4,3-c]pyrazole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-8-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(4-fluorophenyl)-4,5-dihydr-
o-1H-indazole
4-(Isothiazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane
4-[(5-Bromoisothiazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5-dihydro-1H-benzo[g]indazo-
le
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,5-dihydroisochromeno[4,3--
c]pyrazole
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5-dihydro-1H-pyra-
zolo[3,4-f]quinoline
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-[(3S)-3-methoxypyrrolidin-1-
-yl]-1,4-dihydrochromeno[4,3-c]pyrazole
7-Bromo-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4-
,3-c]pyrazole, and tautomers thereof, and pharmaceutically
acceptable salts thereof, and wherein if the compound exhibits
chirality said compound can be in the form of a mixture of
enantiomers or a mixture of diastereomers, or said compound can be
in the form of a single enantiomer or a single diastereomer.
44. A compound according to claim 42, wherein said compound is
selected from:
4-[(4-Chloro-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e,
4-[(4-nitro-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
4-[(5-Methyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
4-(1H-pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane,
4-{[5-(4-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]-
nonane,
4-[(5-Phenylisoxazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
4-{[5-(2-thienyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonane-
,
4-[(5-Phenyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
4-[(5-Cyclopropyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane-
,
4-{[5-(3-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2-
]nonane,
4-(1,4,5,6-Tetrahydrocyclopenta[c]pyrazol-3-ylcarbonyl)-1,4-diaza-
bicyclo[3.2.2]nonane,
4-{[5-(2-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]-
nonane,
4-[(4-Bromo-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e, 3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)isothiazol-4-amine,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4,3-c]pyr-
azole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5,6,7,8,9-hexahydro-1-
H-cycloocta[c]pyrazole,
4-{[5-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-yl]carbonyl}-1,4-di-
azabicyclo[3.2.2]nonane,
4-{[5-(2-Naphthyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonan-
e,
4-{[5-(3-Thienyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nona-
ne,
4-{[5-(4-Fluorophenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.-
2]nonane,
4-[(5-Pyridin-2-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.-
2.2]nonane,
4-[(5-Pyridin-4-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e,
4-[(5-Pyridin-3-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]non-
ane,
5'-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1-methyl-1H,2'H-3,3'-bip-
yrazole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,4-dihydro-
chromeno[4,3-c]pyrazole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-8-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole, and tautomers thereof, and pharmaceutically
acceptable salts thereof, and wherein if the compound exhibits
chirality said compound can be in the form of a mixture of
enantiomers or a mixture of diastereomers, or said compound can be
in the form of a single enantiomer or a single diastereomer.
45. A compound according to claim 42, wherein said compound is
selected from:
(1H-Pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane
hydrochloride, and
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4,3-c]pyr-
azole hydrochloride, and tautomers thereof, and pharmaceutically
acceptable salts thereof, and wherein if the compound exhibits
chirality said compound can be in the form of a mixture of
enantiomers or a mixture of diastereomers, or said compound can be
in the form of a single enantiomer or a single diastereomer.
46. A pharmaceutical composition comprising a compound according to
any one of claims 1 to 45, and a pharmaceutically acceptable
carrier.
47. A pharmaceutical composition according to claim 46, further
comprising at least one additional active agent, wherein said
additional active agent is another a-7 agonist, a PDE4 inhibitor, a
calcium channel blocker, a muscarinic m1 or m2 modulator, an
adenosine receptor modulator, an ampakine, an NMDA-R modulator, an
mGluR modulator, a dopamine modulator, a serotonin modulator, a
cannabinoid modulator, a cholinesterase inhibitors, an agent for
treatment of ADHD, an anti-depressant, anti-inflammatory agent,
ananti-psychotic agent, a beta secretase modulator, a bipolar
disorder agent, a GABA-nergic drug, a gamma secretase modulator, a
histamine H3, a kinase inhibitor, a MAO-B inhibitor, a mood
stabilizer, a 5HT4 modulating agent, a 5HT6 antagonist, or an
.alpha.4.beta.2 modulating agent.
48. A method of treating a patient suffering from a psychotic
disease, a neurodegenerative disease involving a dysfunction of the
cholinergic system, and/or a condition of memory and/or cognition
impairment, comprising administering to the patient an effective
amount of a compound according to any one of claims 1 to 45.
49. A method according to claim 48, wherein said patient is
suffering from schizophrenia, anxiety, mania, depression, or manic
depression.
50. A method according to claim 48, wherein said patient is
suffering from Tourette's syndrome, Parkinson's disease, or
Huntington's .
51. A method according to claim 48, wherein said patient is
suffering from Alzheimer's disease, Lewy Body Dementia, Amyotrophic
Lateral Sclerosis, memory impairment, memory loss, cognition
deficit, attention deficit, or Attention Deficit Hyperactivity
Disorder.
52. A method according to claim 48, wherein said patient is
suffering from Alzheimer's diseases, Pick's disease, diffuse Lewy
Body disease, progressive supranuclear palsy (Steel-Richardson
syndrome), multisystem degeneration (Shy-Drager syndrome), motor
neuron diseases including amyotrophic lateral sclerosis (ALS),
degenerative ataxias, cortical basal degeneration,
ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing
panencephalitis, Huntington's disease, Parkinson's disease,
synucleinopathies, primary progressive aphasia, striatonigral
degeneration, Machado-Joseph disease/spinocerebellar ataxia type 3,
olivopontocerebellar degenerations, Gilles De La Tourette's
disease, bulbar palsy, pseudobulbar palsy, spinal muscular atrophy,
spinobulbar muscular atrophy (Kennedy's disease), primary lateral
sclerosis, familial spastic paraplegia, Werdnig-Hoffmann disease,
Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease,
familial spastic disease, Wohlfart-Kugelberg-Welander disease,
spastic paraparesis, progressive multifocal leu koencephalopathy,
Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease,
Kuru, or fatal familial insomnia.
53. A method according to claim 48, wherein said patient is
suffering froma neurodegenerative disorder resulting from cerebral
ischemia, infarction, intracranial hemorrhage, or intracranial and
intravertebral lesions.
54. A method according to claim 48, wherein said patient is
suffering from age-related dementia or other dementia, or
conditions with memory loss.
55. A method according to claim 48, wherein said patient is
suffering from memory impairment due to Alzheimer's disease, mild
cognitive impairment due to aging, schizophrenia, Parkinson's
disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob
disease, depression, aging, head trauma, stroke, CNS hypoxia,
cerebral senility, multiinfarct dementia, HIV, or cardiovascular
disease.
56. A method according to claim 48, wherein said patient is
suffering from memory impairment as a result of chemotherapy,
kidney dialysis, post-operative surgery, or a bipolar disorder.
57. A method according to claim 48, wherein said patient is
suffering from dementia due to Alzheimer's disease.
58. A method according to claim 48, wherein said patient is
suffering from hereditary cerebral angiopathy, nonneuropathic
hereditary amyloid, Down's syndrome, macroglobulinemia, secondary
familial Mediterranean fever, Muckle-Wells syndrome, multiple
myeloma, pancreatic- or cardiac-related amyloidosis, chronic
hemodialysis anthropathy, Finnish amyloidosis , or Iowa
amyloidosis.
59. A method of treating a patient for alcohol withdrawal or
treating a patient with anti-intoxication therapy comprising
administering to the patient an effective amount of a compound
according to any one of claims 1 to 45.
60. A method of treating a patient suffering from nicotine
addiction, pain, jetlag, obesity and/or diabetes, or a method of
inducing smoking cessation in a patient comprising administering to
the patient an effective amount of a compound according to any one
of claims 1 to 45.
60. A method of treating a patient suffering from inflammation
comprising administering to the patient an effective amount of a
compound according to any one of claims 1 to 45.
61. A method according to claim 60, wherein said inflammation is
due to rheumatoid arthritis, diabetes, sepsis, an autoimmune
disease, fibromyalgia, or ulcerative colitis.
Description
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 60/981,643, filed Oct. 22, 2007, and the
benefit of U.S. Provisional Application Ser. No. 61/050,366, the
entire disclosures of which are hereby incorporated by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to the field of
ligands for nicotinic acetylcholine receptors (nAChR), activation
of nAChRs, and the treatment of disease conditions associated with
defective or malfunctioning nicotinic acetylcholine receptors,
especially of the brain. Further, this invention relates to novel
compounds, which act as ligands for the .alpha.7 nAChR subtype,
methods of preparing such compounds, compositions comprising such
compounds, and methods of use.
BACKGROUND
[0003] There are two types of receptors for the neurotransmitter,
acetylcholine: muscarinic receptors and nicotinic receptors, based
on the selectivity of action of muscarine and nicotine,
respectively. Muscarinic receptors are G-protein coupled receptors.
Nicotinic receptors are members of the ligand-gated ion channel
family. When activated, the conductance of ions across the
nicotinic ion channels increases.
[0004] Nicotinic alpha-7 receptor protein forms a homo-pentameric
channel in vitro that is highly permeable to a variety of cations
(e.g., Ca.sup.++). Each nicotinic alpha-7 receptor has four
transmembrane domains, named M1, M2, M3, and M4. The M2 domain has
been suggested to form the wall lining the channel. Sequence
alignment shows that nicotinic alpha-7 is highly conserved during
evoluion. The M2 domain that lines the channel is identical in
protein sequence from chicken to human. For discussions of the
alpha-7 receptor, see, e.g., Revah et al. (1991), Nature, 353,
846-849; Galzi et al. (1992), Nature 359, 500-505; Fucile et al.
(2000), PNAS 97(7), 3643-3648; Briggs et al. (1999), Eur. J.
Pharmacol. 366 (2-3), 301-308; and Gopalakrishnan et al. (1995),
Eur. J. Pharmacol. 290(3), 237-246.
[0005] The nicotinic alpha-7 receptor channel is expressed in
various brain regions and is believed to be involved in many
important biological processes in the central nervous system (CNS),
including learning and memory. Nicotinic alpha-7 receptors are
localized on both presynaptic and postsynaptic terminals and have
been suggested to be involved in modulating synaptic transmission.
It is therefore of interest to develop novel compounds, which act
as ligands for the .alpha.7 nAChR subtype, for the treatment of
disease conditions associated with defective or malfunctioning
nicotinic acetylcholine receptors.
SUMMARY OF THE INVENTION
[0006] This invention relates to novel compounds, which act as
ligands for the .alpha.7 nAChR subtype, methods of preparing such
compounds, compositions comprising such compounds, and methods of
use thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0007] The invention includes novel compounds of Formula (I):
##STR00002## [0008] wherein [0009] X is NH, N(CH.sub.3), S or O;
[0010] R.sup.1 and R.sup.2 are each, independently, hydrogen,
C.sub.1-C.sub.6-alkyl which is unsubstituted or substituted one or
more times by R.sup.10, C.sub.2-C.sub.6-alkenyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.2-C.sub.6-alkynyl which is unsubstituted or substituted one
or more times by R.sup.10, C.sub.3-C.sub.6-cycloalkyl which is
unsubstituted or substituted one or more times by R.sup.11,
C.sub.3-C.sub.8-cycloalkenyl which is unsubstituted or substituted
one or more times by R.sup.11, halo, OR.sup.3, SR.sup.3,
NR.sup.3R.sup.4, aryl which is unsubstituted or substituted one or
more times by R.sup.12, heterocyclyl which is unsubstituted or
substituted one or more times by R.sup.12, S(O).sub.pR.sup.13,
S(O).sub.pNR.sup.3R.sup.4, --C(O)R.sup.3, --C(O)OR.sup.3,
--C(O)NR.sup.3R.sup.4, NO.sub.2, or CN, or [0011] R.sup.1 and
R.sup.2 taken together are
##STR00003##
[0011] --(CH.sub.2).sub.2CR.sup.9.dbd.CR.sup.9--, or
--(CH.sub.2).sub.m; [0012] R.sup.3 and R.sup.4 are each,
independently, hydrogen, C.sub.1-C.sub.6-alkyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.3-C.sub.6-alkenyl which is unsubstituted or substituted one
or more times by R.sup.10, C.sub.3-C.sub.6-alkynyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.3-C.sub.6-cycloalkyl which is unsubstituted or substituted
one or more times by R.sup.11, C.sub.3-C.sub.6-cycloalkenyl which
is unsubstituted or substituted one or more times by R.sup.11, aryl
which is unsubstituted or substituted one or more times by
R.sup.12, heterocyclyl which is unsubstituted or substituted one or
more times by R.sup.12, --C(O)R.sup.5, --C(O)OR.sup.5, or
--C(O)NR.sup.5R.sup.6; [0013] W.sup.1, W.sup.2, W.sup.3 and W.sup.4
are each, independently, CR.sup.7 or N, wherein no more than one of
W.sup.1, W.sup.2, W.sup.3 and W.sup.4 is N; [0014] V.sup.1 and
V.sup.2 are each, independently, O, CR.sup.8R.sup.8, S, NH, or
NR.sup.3, provided that when one of V.sup.1 or V.sup.2 represent O,
S, NH, or NR.sup.3, the other is CR.sup.8R.sup.8; [0015] m is 3, 4,
5, or 6; [0016] n is 0, 1 or 2; [0017] p is 1 or 2; [0018] R.sup.5
and R.sup.6 are each, independently, hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.8-cycloalkenyl, aryl, or heterocyclyl; [0019] R.sup.7
is hydrogen, C.sub.1-C.sub.6-alkyl which is unsubstituted or
substituted one or more times by R.sup.10, C.sub.2-C.sub.6-alkenyl
which is unsubstituted or substituted one or more times by
R.sup.10, C.sub.2-C.sub.6-alkynyl which is unsubstituted or
substituted one or more times by R.sup.10,
C.sub.3-C.sub.6-cycloalkyl which is unsubstituted or substituted
one or more times by R.sup.11, C.sub.3-C.sub.6-cycloalkenyl which
is unsubstituted or substituted one or more times by R.sup.11,
halo, OR.sup.3, SR.sup.3, NR.sup.3R.sup.4, aryl which is
unsubstituted or substituted one or more times by R.sup.12,
heterocyclyl which is unsubstituted or substituted one or more
times by R.sup.12, S(O).sub.pR.sup.13, S(O).sub.pNR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3R.sup.4, --NO.sub.2, or CN; [0020]
R.sup.8 is, in each case independently, [0021] H, [0022]
C.sub.1-C.sub.6-alkyl which is unsubstituted or substituted one or
more times by C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy,
OH, halo or NR.sup.3R.sup.4, [0023] O--C.sub.1-C.sub.6-alkyl,
[0024] OH, [0025] halo, or [0026] NR.sup.3R.sup.4, [0027] or two
R.sup.B together may represent oxo; [0028] R.sup.9 is, in each case
independently, hydrogen, C.sub.1-C.sub.6-alkyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.2-C.sub.6-alkenyl which is unsubstituted or substituted one
or more times by R.sup.10, C.sub.2-C.sub.6-alkynyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.3-C.sub.6-cycloalkyl which is unsubstituted or substituted
one or more times by R.sup.11, C.sub.3-C.sub.8-cycloalkeny which is
unsubstituted or substituted one or more times by R.sup.11, aryl
which is unsubstituted or substituted one or more times by
R.sup.12, or heterocyclyl which is unsubstituted or substituted one
or more times by R.sup.12; [0029] R.sup.10 is, in each case
independently, halogen, C.sub.2-C.sub.7-alkoxycarbonyl, hydroxy,
C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy,
C.sub.3-C.sub.6-alkenyloxy, C.sub.3-C.sub.6-alkynyloxy, nitro,
amino, C.sub.1-6-alkylamino, dialkylamino wherein each alkyl group
has independently 1 to 6 carbon atoms, aminocarbonyl,
C.sub.1-6-alkyl-aminocarbonyl, dialkylaminocarbonyl wherein each
alkyl group has independently 1 to 6 carbon atoms, hydroxyalkyl
having 1 to 6 carbon atoms, hydroxyalkoxy having 1 to 6 carbon
atoms, carboxy, cyano, formyl, alkanoyl having 2 to 7 carbon atoms,
benzoyl, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-alkylsulfamoyl,
phenoxy, formyloxy, alkanoyloxy having 2 to 7 carbon atoms, and
benzoyloxy; [0030] R.sup.11 is, in each case independently,
halogen, C.sub.1-C.sub.6-alkyl, halogenated C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkynyl,
C.sub.2-C.sub.7-alkoxycarbonyl, hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-alkynyloxy, nitro, methylenedioxy, ethylenedioxy,
amino, C.sub.1-6-alkylamino, dialkylamino wherein each alkyl group
has independently 1 to 6 carbon atoms, aminocarbonyl,
C.sub.1-6-alkyl-aminocarbonyl, dialkylaminocarbonyl wherein each
alkyl group has independently 1 to 6 carbon atoms, hydroxyalkyl
having 1 to 6 carbon atoms, hydroxyalkoxy having 1 to 6 carbon
atoms, carboxy, cyano, formyl, alkanoyl having 2 to 7 carbon atoms,
benzoyl, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-alkylsulfamoyl,
phenoxy, formyloxy, alkanoyloxy having 2 to 7 carbon atoms, and
benzoyloxy; [0031] R.sup.12 is, in each case independently,
halogen, C.sub.1-C.sub.6-alkyl, halogenated C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.5-C.sub.8-cycloalkenyl,
C.sub.2-C.sub.7-alkoxycarbonyl, hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-alkynyloxy, nitro, methylenedioxy, ethylenedioxy,
amino, C.sub.1-6-alkylamino, dialkylamino wherein each alkyl group
has independently 1 to 6 carbon atoms, aminocarbonyl,
C.sub.1-6-alkyl-aminocarbonyl, dialkylaminocarbonyl wherein each
alkyl group has independently 1 to 6 carbon atoms, hydroxyalkyl
having 1 to 6 carbon atoms, hydroxyalkoxy having 1 to 6 carbon
atoms, carboxy, cyano, formyl, alkanoyl having 2 to 7 carbon atoms,
benzoyl, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-alkylsulfamoyl,
phenoxy, formyloxy, alkanoyloxy having 2 to 7 carbon atoms, and
benzoyloxy; and [0032] R.sup.13 is in each case independently,
C.sub.1-C.sub.6-alkyl which is unsubstituted or substituted one or
more times by R.sup.10, C.sub.3-C.sub.6-alkenyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.3-C.sub.6-alkynyl which is unsubstituted or substituted one
or more times by R.sup.10, C.sub.3-C.sub.6-cycloalkyl which is
unsubstituted or substituted one or more times by R.sup.11,
C.sub.3-C.sub.8-cycloalkenyl which is unsubstituted or substituted
one or more times by R.sup.11, aryl which is unsubstituted or
substituted one or more times by R.sup.12, heterocyclyl which is
unsubstituted or substituted one or more times by R.sup.12,
--C(O)R.sup.5, --C(O)OR.sup.5, or --C(O)NR.sup.5R.sup.6; and
tautomers thereof, pharmaceutically acceptable salts and esters
thereof, and wherein if the compound exhibits chirality it can be
in the form of a mixture of enantiomers such as a racemate or a
mixture of diastereomers, or can be in the form of a single
enantiomer or a single diastereomer.
[0033] Another embodiment of the invention includes novel compounds
of Formula (1) wherein: [0034] R.sup.1 and R.sup.2 are each,
independently, hydrogen, C.sub.1-C.sub.6-alkyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.2-C.sub.6-alkenyl which is unsubstituted or substituted one
or more times by R.sup.10, C.sub.2-C.sub.6-alkynyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.3-C.sub.6-cycloalkyl which is unsubstituted or substituted
one or more times by R.sup.10, C.sub.3-C.sub.8-cycloalkenyl which
is unsubstituted or substituted one or more times by R.sup.10,
halo, OR.sup.3, SR.sup.3, NR.sup.3R.sup.4, aryl which is
unsubstituted or substituted one or more times by R.sup.11,
heterocyclyl which is unsubstituted or substituted one or more
times by R.sup.11, S(O).sub.pR.sup.13, S(O).sub.pNR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4, NO.sub.2, or
CN, or [0035] R.sup.1 and R.sup.2 taken together, are
##STR00004##
[0035] or --(CH.sub.2).sub.m--.
[0036] Another embodiment of the invention includes novel compounds
of Formula (I)
##STR00005## [0037] wherein [0038] X is NH, N(CH.sub.3), S or O;
[0039] R.sup.1 and R.sup.2 are each, independently, hydrogen,
C.sub.1-C.sub.6-alkyl which is unsubstituted or substituted one or
more times by R.sup.10, C.sub.3-C.sub.6-cycloalkyl which is
unsubstituted or substituted one or more times by R.sup.10, halo,
NH.sub.2, phenyl which is unsubstituted or substituted one or more
times by R.sup.11, naphthyl which is unsubstituted or substituted
one or more times by R.sup.11, 1,4-benzodioxan-6-yl which is
unsubstituted or substituted one or more times by R.sup.11, pyridyl
which is unsubstituted or substituted one or more times by
R.sup.11, thienyl which is unsubstituted or substituted one or more
times by R.sup.11, or NO.sub.2, or [0040] R.sup.1 and R.sup.2 taken
together, are
##STR00006##
[0040] or, --(CH.sub.2).sub.m; and [0041] m is 3, 4, 5, or 6; and
tautomers thereof, pharmaceutically acceptable salts and esters
thereof, and wherein if the compound exhibits chirality it can be
in the form of a mixture of enantiomers such as a racemate or a
mixture of diastereomers, or can be in the form of a single
enantiomer or a single diastereomer.
[0042] Another embodiment of the invention includes novel compounds
of
[0043] Formula (1) [0044] R.sup.1 and R.sup.2 are each,
independently, hydrogen, C.sub.1-C.sub.6-alkyl which is
unsubstituted or substituted one or more times by R.sup.10,
C.sub.3-C.sub.6-cycloalkyl which is unsubstituted or substituted
one or more times by R.sup.10, halo, NH.sub.2, phenyl which is
unsubstituted or substituted one or more times by R.sup.11,
naphthyl which is unsubstituted or substituted one or more times by
R.sup.11, 1,4-benzodioxan-6-yl which is unsubstituted or
substituted one or more times by R.sup.11, pyridyl which is
unsubstituted or substituted one or more times by R.sup.11, thienyl
which is unsubstituted or substituted one or more times by
R.sup.11, or NO.sub.2, or [0045] R.sup.1 and R.sup.2 taken
together, are
##STR00007##
[0046] or, --(CH.sub.2).sub.m.
[0047] Radicals which are substituted one or more times preferably
have 1 to 3 substituents, especially 1 or 2 substituents of the
exemplified substituents. Halogenated radicals such as halogenated
alkyls are preferably fluorinated and include perhalo radicals such
as trifluoromethyl.
[0048] The terms identified above have the following meanings
throughout: Alkyl throughout means a straight-chain or
branched-chain aliphatic hydrocarbon radical having preferably 1 to
6 carbon atoms, particularly 1 to 4 carbon atoms, unless otherwise
indicated. Suitable alkyl groups include methyl, ethyl, propyl,
isopropyl, butyl, sec-butyl, and tert-butyl. Additional suitable
alkyl groups include pentyl, hexyl, 1-, 2- or 3-methylbutyl, 1,1-,
1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-, 3- or
4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl,
1- or 2-ethylbutyl, ethylmethylpropyl, trimethylpropyl, and the
like. A halogenated alkyl group is an alkyl group which is
substituted one or more times by halo (F, Cl, Br, or I). For
example, the halogenated alkyl group may be an alkyl group which is
substituted one or more times by F (e.g., CF.sub.3, and
CHF.sub.2).
[0049] When an alkyl group is "substituted," unless indicated
otherwise, it is substituted (i.e., a hydrogen atom may be replaced
by a substituent group) one or more times by R.sup.10 groups, i.e.,
halogen, C.sub.2-C.sub.7-alkoxycarbonyl, hydroxy,
C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy,
C.sub.3-C.sub.6-alkenyloxy, C.sub.3-C.sub.6-alkynyloxy, nitro,
amino, C.sub.1-6-alkylamino, dialkylamino wherein each alkyl group
has independently 1 to 6 carbon atoms, aminocarbonyl,
C.sub.1-6-alkyl-aminocarbonyl, dialkylaminocarbonyl wherein each
alkyl group has independently 1 to 6 carbon atoms, hydroxyalkyl
having 1 to 6 carbon atoms, hydroxyalkoxy having 1 to 6 carbon
atoms, carboxy, cyano, formyl, alkanoyl having 2 to 7 carbon atoms,
benzoyl, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-alkylsulfamoyl,
phenoxy, formyloxy, alkanoyloxy having 2 to 7 carbon atoms (e.g.,
acetoxy), and benzoyloxy. For example, where indicated alkyl groups
can be substituted by halogen, hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy, cyano, nitro, amino,
C.sub.1-C.sub.6-alkylamino, and di-C.sub.1-C.sub.6-alkylamino.
[0050] Alkenyl throughout means a straight-chain or branched-chain
alkyl radical having preferably 2 to 6 carbon atoms, unless
otherwise indicated, wherein at least one CH.sub.2CH.sub.2 group is
replaced by CH=CH. Suitable alkenyl groups include ethenyl,
1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
1,3-butadienyl, and 3-methyl-2-butenyl, etc.
[0051] When an alkenyl group is "substituted," unless indicated
otherwise, it is substituted (i.e., a hydrogen atom may be replaced
by a substituent group) one or more times by R.sup.10 groups, i.e.,
halogen, C.sub.2-C.sub.7alkoxycarbonyl, hydroxy,
C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy,
C.sub.3-C.sub.6-alkenyloxy, C.sub.3-C.sub.6-alkynyloxy, nitro,
amino, C.sub.1-6-alkylamino, dialkylamino wherein each alkyl group
has independently 1 to 6 carbon atoms, aminocarbonyl,
C.sub.1-6-alkyl-aminocarbonyl, dialkylaminocarbonyl wherein each
alkyl group has independently 1 to 6 carbon atoms, hydroxyalkyl
having 1 to 6 carbon atoms, hydroxyalkoxy having 1 to 6 carbon
atoms, carboxy, cyano, formyl, alkanoyl having 2 to 7 carbon atoms,
benzoyl, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-alkylsulfamoyl,
phenoxy, formyloxy, alkanoyloxy having 2 to 7 carbon atoms (e.g.,
acetoxy), and benzoyloxy. For example, where indicated alkyl groups
can be substituted by halogen, hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy, cyano, nitro, amino,
C.sub.1-C.sub.6-alkylamino, and di-C.sub.1-C.sub.6-alkylamino.
[0052] Alkynyl throughout means a straight-chain or branched-chain
alkyl radical having preferably 2 to 6 carbon atoms, unless
otherwise indicated, wherein at least one CH.sub.2CH.sub.2 group is
replaced by C.ident.C. Suitable alkynyl groups include ethynyl,
propynyl, butynyl, etc.
[0053] When an alkynyl group is "substituted," unless indicated
otherwise, it is substituted (i.e., a hydrogen atom may be replaced
by a substituent group) one or more times by R.sup.10 groups, i.e.,
halogen, C.sub.2-C.sub.7-alkoxycarbonyl, hydroxy,
C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy,
C.sub.3-C.sub.6-alkenyloxy, C.sub.3-C.sub.6-alkynyloxy, nitro,
amino, C.sub.1-6-alkylamino, dialkylamino wherein each alkyl group
has independently 1 to 6 carbon atoms, aminocarbonyl,
C.sub.1-6-alkyl-aminocarbonyl, dialkylaminocarbonyl wherein each
alkyl group has independently 1 to 6 carbon atoms, hydroxyalkyl
having 1 to 6 carbon atoms, hydroxyalkoxy having 1 to 6 carbon
atoms, carboxy, cyano, formyl, alkanoyl having 2 to 7 carbon atoms,
benzoyl, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-alkylsulfamoyl,
phenoxy, formyloxy, alkanoyloxy having 2 to 7 carbon atoms (e.g.,
acetoxy), and benzoyloxy. For example, where indicated alkyl groups
can be substituted by halogen, hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy, cyano, nitro, amino,
C.sub.1-C.sub.6-alkylamino, and di-C.sub.1-C.sub.6-alkylamino.
[0054] Alkoxy means alkyl-O-- groups in which the alkyl portion has
preferably 1 to 6 carbon atoms, especially 1 to 4 carbon atoms,
unless otherwise indicated. Suitable alkoxy groups or
O--C.sub.1-C.sub.6-alkyl groups include methoxy, ethoxy, propoxy,
isopropoxy, isobutoxy, and sec-butoxy. The haloalkoxy group is an
alkoxy group which is substituted one or more times by halo (F, Cl,
Br, or I). For example, the alkoxy group may be substituted one or
more times by F (e.g., OCF.sub.3, and OCHF.sub.2).
[0055] Aryl, as a group or substituent per se or as part of a group
or substituent, refers to an aromatic carbocyclic radical
containing 6 to 12 carbon atoms, unless indicated otherwise.
Suitable aryl groups include phenyl, naphthyl and biphenyl. Phenyl
is preferred.
[0056] When an aryl group is "substituted," unless indicated
otherwise, it is substituted (i.e., a hydrogen atom may be replaced
by a substituent group) one or more times by R.sup.12 groups, i.e.,
halogen, C.sub.1-C.sub.6-alkyl, halogenated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.5-C.sub.8-cycloalkenyl,
C.sub.2-C.sub.7-alkoxycarbonyl, hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-alkynyloxy, nitro, methylenedioxy, ethylenedioxy,
amino, C.sub.1-6-alkylamino, dialkylamino wherein each alkyl group
has independently 1 to 6 carbon atoms, aminocarbonyl,
C.sub.1-6-alkyl-aminocarbonyl, dialkylaminocarbonyl wherein each
alkyl group has independently 1 to 6 carbon atoms, hydroxyalkyl
having 1 to 6 carbon atoms, hydroxyalkoxy having 1 to 6 carbon
atoms, carboxy, cyano, formyl, alkanoyl having 2 to 7 carbon atoms,
benzoyl, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-alkylsulfamoyl,
phenoxy, formyloxy, alkanoyloxy having 2 to 7 carbon atoms (e.g.,
acetoxy), and benzoyloxy. Preferred substituents for the aryl
groups include, for example, halogen, phenyl,
C.sub.1-C.sub.6-alkyl, halogenated C.sub.1-C.sub.6-alkyl (e.g.,
trifluoromethyl), hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy, cyano, nitro, amino,
C.sub.1-C.sub.6-alkylamino, and di-C.sub.1-C.sub.6-alkylamino.
[0057] Cycloalkyl means a cyclic, bicyclic or tricyclic saturated
hydrocarbon radical having 3 to 8 carbon atoms, unless otherwise
indicated. Suitable cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl. Other suitable cycloalkyl
groups include spiropentyl, bicyclo[2.2.1]heptyl, and
bicyclo[2.2.2]octyl.
[0058] When an cycloalkyl group is "substituted," unless indicated
otherwise, it is substituted (i.e., a hydrogen atom may be replaced
by a substituent group) one or more times by R.sup.11 groups, i.e.,
halogen, C.sub.1-C.sub.6-alkyl, halogenated C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkynyl,
C.sub.2-C.sub.7-alkoxycarbonyl, hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-alkynyloxy, nitro, methylenedioxy, ethylenedioxy,
amino, C.sub.1-.sub.6-alkylamino, dialkylamino wherein each alkyl
group has independently 1 to 6 carbon atoms, aminocarbonyl,
C.sub.1-6-alkyl-aminocarbonyl, dialkylaminocarbonyl wherein each
alkyl group has independently 1 to 6 carbon atoms, hydroxyalkyl
having 1 to 6 carbon atoms, hydroxyalkoxy having 1 to 6 carbon
atoms, carboxy, cyano, formyl, alkanoyl having 2 to 7 carbon atoms,
benzoyl, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-alkylsulfamoyl,
phenoxy, formyloxy, alkanoyloxy having 2 to 7 carbon atoms (e.g.,
acetoxy), and benzoyloxy. Preferred substituents for the cycloalkyl
groups include, for example, F, Cl, Br, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, hydroxyl, amino, monoalkylamino having 1 to
4 carbon atoms, and/or dialklyamino in which each alkyl group has 1
to 4 carbon atoms.
[0059] Cycloalkenyl throughout means a cyclic, bicyclic or
tricyclic saturated hydrocarbon radical having 3 to 8 carbon atoms,
unless otherwise indicated, wherein at least one CH.sub.2CH.sub.2
group is replaced by CH.dbd.CH. Suitable cycloalkenyl groups
include cyclopentenyl, cyclohexenyl, cyclooctadienyl, etc.
[0060] When an cycloalkenyl group is "substituted," unless
indicated otherwise, it is substituted (i.e., a hydrogen atom may
be replaced by a substituent group) one or more times by R.sup.11
groups, i.e., halogen, C.sub.1-C.sub.a-alkyl, halogenated
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkynyl, C.sub.2-C.sub.7-alkoxycarbonyl, hydroxy,
C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy,
C.sub.3-C.sub.6-alkenyloxy, C.sub.3-C.sub.6-alkynyloxy, nitro,
methylenedioxy, ethylenedioxy, amino, C.sub.1-6-alkylamino,
dialkylamino wherein each alkyl group has independently 1 to 6
carbon atoms, aminocarbonyl, C.sub.1-6-alkyl-aminocarbonyl,
dialkylaminocarbonyl wherein each alkyl group has independently 1
to 6 carbon atoms, hydroxyalkyl having 1 to 6 carbon atoms,
hydroxyalkoxy having 1 to 6 carbon atoms, carboxy, cyano, formyl,
alkanoyl having 2 to 7 carbon atoms, benzoyl,
C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-alkylsulfamoyl,
phenoxy, formyloxy, alkanoyloxy having 2 to 7 carbon atoms (e.g.,
acetoxy), and benzoyloxy. Preferred substituents for the
cycloalkenyl groups include, for example, F, Cl, Br,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, hydroxyl, amino,
monoalkylamino having 1 to 4 carbon atoms, and/or dialklyamino in
which each alkyl group has 1 to 4 carbon atoms.
[0061] Halo means F, Cl, Br, or I.
[0062] Heterocyclyl groups refer to saturated, partially saturated
and fully unsaturated (i.e., heteroaryl) heterocyclic ring radicals
having one, two or three rings, preferably 1 to 2 rings, and a
total number of 5 to 14 ring atoms, preferably 5 to 10 ring atoms,
wherein at least one of the ring atoms is an N, O or S atom.
Preferably, the heterocyclyl group contains 1 to 4 hetero-ring
atoms selected from N, O and S, for example, 1 or 2 heteroatoms.
Suitable saturated and partially saturated heterocyclyl groups
include, but are not limited to tetrahydrofuranyl,
tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl, oxoazolinyl, isoxazolinyl
and the like. Suitable heteroaryl groups include but are not
limited to furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,
pyridyl, pyrimidinyl, benzopyranyl, indolyl, quinolinyl,
isoquinolinyl, naphthyridinyl and the like. Other examples of
suitable heterocyclyl groups, are 2-quinolinyl, 1,3-benzodioxyl,
2-thienyl, 2-benzofuranyl, 2-benzothiophenyl, 3-thienyl,
2,3-dihydro-5-benzofuranyl, 4-indoyl, 4-pyridyl, 3-quinolinyl,
4-quinolinyl, 1,4-benzodioxan-6-yl, 3-indoyl, 2-pyrrolyl,
benzopyran-6-yl, 5-indolyl, 1,5-benzoxepin-8-yl, 3-pyridyl,
6-coumarinyl, 5-benzofuranyl, 2-isoimidazol-4-yl, 3-pyrazolyl,
3-carbazolyl, 2-thiazolyl, 2-oxazolyl, 1-imidazolyl, and
2-imidazolyl.
[0063] When a heterocyclyl group is characterized as "optionally
substituted", it can be substituted (i.e., a hydrogen atom may be
replaced by a substituent group) one or more times by suitable
substituents including halogen, C.sub.1-C.sub.6-alkyl, halogenated
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.8-alkynyl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.5-C.sub.8-cycloalkenyl, C.sub.2-C.sub.7-alkoxycarbonyl,
hydroxy, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy,
C.sub.3-C.sub.6-alkenyloxy, C.sub.3-C.sub.6-alkynyloxy, nitro,
methylenedioxy, ethylenedioxy, amino, C dialkylamino wherein each
alkyl group has independently 1 to 6 carbon atoms, aminocarbonyl,
C.sub.1-6-alkyl-aminocarbonyl, dialkylaminocarbonyl wherein each
alkyl group has independently 1 to 6 carbon atoms, hydroxyalkyl
having 1 to 6 carbon atoms, hydroxyalkoxy having 1 to 6 carbon
atoms, carboxy, cyano, formyl, alkanoyl having 2 to 7 carbon atoms,
benzoyl, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-alkylsulfamoyl, aryl
having 6 to 12 carbon atoms, phenoxy, formyloxy, alkanoyloxy having
2 to 7 carbon atoms (e.g., acetoxy), and benzoyloxy. Preferred
substituents for the heterocyclyl groups include, for example,
halogen, phenyl, C.sub.1-C.sub.6-alkyl, halogenated
C.sub.1-C.sub.6-alkyl (e.g., trifluoromethyl), hydroxy,
C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, cyano, nitro,
oxo, amino, C.sub.1-C.sub.6-alkylamino, and
di-C.sub.1-C.sub.6-alkylamino.
[0064] According to a further aspect of the invention, R.sup.1 and
R.sup.2 are each independently H, F, Cl, Br, cyano, methyl, ethyl,
propyl, hydroxy, methoxy, ethoxy, nitro, amino, methylamino,
ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclopentyl,
cyclohexyl, acetyl, propionyl, acetoxy, methoxycarbonyl,
ethoxycarbonyl, carbamoyl (NH.sub.2--CO--), phenyl, methylphenyl,
ethyiphenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl,
chlorophenyl, aminophenyl, cyanophenyl, nitrophenyl, naphthyl,
pyridyl, methylpyridyl, ethylpyridyl, methoxypyridyl,
ethoxypyridyl, fluoropyridyl, chioropyridyl, aminopyridyl,
cyanopyridyl, nitropyridyl, thienyl, methylthienyl, fluorothienyl,
chlorothienyl, pyazole, or methylpyrazole.
[0065] According to a further aspect of the invention, R.sup.1 is
H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy, methoxy,
ethoxy, nitro, amino, methylamino, ethylamino, dimethylamino,
diethylamino, cyclopropyl, cyclopentyl, cyclohexyl, acetyl,
propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or carbamoyl
(NH.sub.2--CO--), and/or R.sup.2 is H, F, Cl, Br, cyano, methyl,
ethyl, propyl, hydroxy, methoxy, ethoxy, nitro, amino, methylamino,
ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclopentyl,
cyclohexyl, acetyl, propionyl, acetoxy, methoxycarbonyl,
ethoxycarbonyl, carbamoyl (NH.sub.2--CO--), phenyl, methylphenyl,
ethylphenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl,
chlorophenyl, aminophenyl, cyanophenyl, nitrophenyl, naphthyl,
pyridyl, methylpyridyl, ethylpyridyl, methoxypyridyl,
ethoxypyridyl, fluoropyridyl, chloropyridyl, aminopyridyl,
cyanopyridyl, nitropyridyl, thienyl, methyithienyl, fluorothienyl,
chlorothienyl, pyazole, or methylpyrazole.
[0066] According to a further aspect of the invention, R.sup.1 is
H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy, methoxy,
ethoxy, nitro, amino, methylamino, ethylamino, dimethylamino,
diethylamino, cyclopropyl, cyclopentyl, cyclohexyl, acetyl,
propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or carbamoyl
(NH.sub.2--CO--), and/or R.sup.2 is phenyl, methylphenyl,
ethylphenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl,
chlorophenyl, aminophenyl, cyanophenyl, nitrophenyl, naphthyl,
pyridyl, methylpyridyl, ethylpyridyl, methoxypyridyl,
ethoxypyridyl, fluoropyridyl, chloropyridyl, aminopyridyl,
cyanopyridyl, nitropyridyf, thienyl, methyithienyl, fluorothienyl,
chlorothienyl, pyazole, or methylpyrazole.
[0067] According to a further aspect of the invention, R.sup.1 and
R.sup.2 together are --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
--(CH.sub.2).sub.5--, or --(CH.sub.2).sub.6--, especially
--(CH.sub.2).sub.3-- or --(CH.sub.2).sub.6--.
[0068] According to a further aspect of the invention, R.sup.1 and
R.sup.2 together are
##STR00008##
[0069] According to a further aspect of the invention, X is
preferably NH, S or O, especially O.
[0070] According to a further aspect, the invention relates to
compounds of Formula Ia:
##STR00009##
wherein X, R.sup.1, and R.sup.2 are as defined in Formula I.
[0071] According to a further aspect, the invention relates to
compounds of Formula la wherein R.sup.1 and R.sup.2 are each
independently H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy,
methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl,
carbamoyl (NH.sub.2--CO--), phenyl, methylphenyl, ethylphenyl,
methoxyphenyl, ethoxyphenyl, fluorophenyl, chlorophenyl,
aminophenyl, cyanophenyl, nitrophenyl, naphthyl, pyridyl,
methylpyridyl, ethylpyridyl, methoxypyridyl, ethoxypyridyl,
fluoropyridyl, chloropyridyl, aminopyridyl, cyanopyridyl,
nitropyridyl, thienyl, methylthienyl, fluorothienyl, chlorothienyl,
pyazole, or methylpyrazole.
[0072] According to a further aspect, the invention relates to
compounds of Formula la wherein R.sup.1 is H, F, Cl, Br, cyano,
methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, nitro, amino,
methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl,
cyclopentyl, cyclohexyl, acetyl, propionyl, acetoxy,
methoxycarbonyl, ethoxycarbonyl, or carbamoyl (NH.sub.2--CO--),
and/or R.sup.2 is H, F, Cl, Br, cyano, methyl, ethyl, propyl,
hydroxy, methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl,
carbamoyl (NH.sub.2--CO--), phenyl, methylphenyl, ethylphenyl,
methoxyphenyl, ethoxyphenyl, fluorophenyl, chlorophenyl,
aminophenyl, cyanophenyl, nitrophenyl, naphthyl, pyridyl,
methylpyridyl, ethylpyridyl, methoxypyridyl, ethoxypyridyl,
fluoropyridyl, chloropyridyl, aminopyridyl, cyanopyridyl,
nitropyridyl, thienyl, methylthienyl, fluorothienyl, chlorothienyl,
pyazole, or methylpyrazole.
[0073] According to a further aspect, the invention relates to
compounds of Formula Ia wherein R.sup.1 is H, F, Cl, Br, cyano,
methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, nitro, amino,
methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl,
cyclopentyl, cyclohexyl, acetyl, propionyl, acetoxy,
methoxycarbonyl, ethoxycarbonyl, and carbamoyl (NH.sub.2--CO--),
and/or R.sup.2 is selected from phenyl, methylphenyl, ethylphenyl,
methoxyphenyl, ethoxyphenyl, fluorophenyl, chlorophenyl,
aminophenyl, cyanophenyl, nitrophenyl, naphthyl, pyridyl,
methylpyridyl, ethylpyridyl, methoxypyridyl, ethoxypyridyl,
fluoropyridyl, chloropyridyl, aminopyridyl, cyanopyridyl,
nitropyridyl, thienyl, methylthienyl, fluorothienyl, chlorothienyl,
pyazole, or methylpyrazole.
[0074] According to a further aspect, the invention relates to
compounds of Formula Ia wherein R.sup.1 and R.sup.2 together are
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--,
or --(CH.sub.2).sub.6--, especially --(CH.sub.2).sub.3-- or
--(CH.sub.2).sub.6--.
[0075] According to a further aspect; the invention relates to
compounds of Formula Ib:
##STR00010##
wherein X, R.sup.1, and R.sup.2 are as defined in Formula I.
[0076] According to a further aspect, the invention relates to
compounds of Formula Ib wherein R.sup.1 and R.sup.2 are each
independently H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy,
methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl,
carbamoyl (NH.sub.2--CO--), phenyl, methylphenyl, ethylphenyl,
methoxyphenyl, ethoxyphenyl, fluorophenyl, chlorophenyl,
aminophenyl, cyanophenyl, or nitrophenyl.
[0077] According to a further aspect, the invention relates to
compounds of Formula Ic:
##STR00011##
wherein X, R.sup.1, and R.sup.2 are as defined in Formula I.
[0078] According to a further aspect, the invention relates to
compounds of Formula Ic wherein R.sup.1 and R.sup.2 are each
independently H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy,
methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl,
carbamoyl (NH.sub.2--CO--), phenyl, methylphenyl, ethylphenyl,
methoxyphenyl, ethoxyphenyl, fluorophenyl, chiorophenyl,
aminophenyl, cyanophenyl, or nitrophenyl.
[0079] According to a further aspect, the invention relates to
compounds of Formula Id:
##STR00012##
wherein R.sup.7 is as defined in Formula I.
[0080] According to a further aspect, the invention relates to
compounds of Formula Id wherein R.sup.7 is in each case
independently H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy,
methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl,
carbamoyl (NH.sub.2--CO--), or optionally substituted heterocyclyl
(e.g., methoxypyrrolidinyl).
[0081] According to a further aspect, the invention relates to
compounds of Formula Id wherein there is only one R.sup.7 group and
it is H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy, methoxy,
ethoxy, nitro, amino, methylamino, ethylamino, dimethylamino,
diethylamino, cyclopropyl, cyclopentyl, cyclohexyl, acetyl,
propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or carbamoyl
(NH.sub.2--CO--).
[0082] According to a further aspect, the invention relates to
compounds of Formula Id wherein R.sup.7 is in each case
independently H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy,
methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
[0083] According to a further aspect, the invention relates to
compounds of Formula Ie:
##STR00013##
wherein R.sup.7 is as defined in Formula I.
[0084] According to a further aspect, the invention relates to
compounds of Formula Ie wherein R.sup.7 is in each case
independently H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy,
methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
[0085] According to a further aspect, the invention relates to
compounds of Formula Ie wherein R.sup.7 is in each case
independently H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy,
methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
[0086] According to a further aspect, the invention relates to
compounds of Formula If:
##STR00014##
wherein R.sup.7 is as defined in Formula I.
[0087] According to a further aspect, the invention relates to
compounds of Formula If wherein R.sup.7 is in each case
independently H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy,
methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
[0088] According to a further aspect, the invention relates to
compounds of Formula If wherein R.sup.7 is in each case
independently H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy,
methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
[0089] According to a further aspect, the invention relates to
compounds of Formula Ig:
##STR00015##
wherein R.sup.7 is as defined in Formula I.
[0090] According to a further aspect, the invention relates to
compounds of Formula Ig wherein R.sup.7 is in each case
independently H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy,
methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
[0091] According to a further aspect, the invention relates to
compounds of Formula Ig wherein R.sup.7 is in each case
independently H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy,
methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
[0092] According to a further aspect, the invention relates to
compounds of Formula Ih:
##STR00016##
wherein, R.sup.9 is as defined in Formula I.
[0093] According to a further aspect, the invention relates to
compounds of Formula Ih wherein R.sup.9 is in each case
independently H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy,
methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
[0094] According to a further aspect, the invention relates to
compounds of Formula Ih wherein R.sup.9 is in each case
independently H, F, Cl, Br, cyano, methyl, ethyl, propyl, hydroxy,
methoxy, ethoxy, nitro, amino, methylamino, ethylamino,
dimethylamino, diethylamino, cyclopropyl, cyclopentyl, cyclohexyl,
acetyl, propionyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, or
carbamoyl (NH.sub.2--CO--).
[0095] According to a further aspect, the invention relates to the
following compounds of Formula I: [0096]
4-[(4-Chloro-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
[0097]
4-[(4-nitro-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e, [0098]
4-[(5-Methyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]no-
nane, [0099]
4-(1H-pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane, [0100]
4-{[5-(4-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo-
[3.2.2]nonane, [0101]
4-[(5-Phenylisoxazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
[0102]
4-{[5-(2-thienyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonane-
, [0103]
4-[(5-Phenyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]non-
ane, [0104]
4-[(5-Cyclopropyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane-
, [0105]
4-{[5-(3-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicycl-
o[3.2.2]nonane, [0106]
4-(1,4,5,6-Tetrahydrocyclopenta[c]pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[-
3.2.2]nonane, [0107]
4-{[5-(2-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]-
nonane, [0108]
4-[(4-Bromo-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
[0109]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)isothiazol-4-amine,
[0110]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4,-
3-c]pyrazole, [0111]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5,6,7,8,9-hexahydro-1H-cycl-
oocta[c]pyrazole, [0112]
4-{[5-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-yl]carbonyl}-1,4-di-
azabicyclo[3.2.2]nonane, [0113]
4-{[5-(2-Naphthyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonan-
e, [0114]
4-{[5-(3-Thienyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2-
.2]nonane, [0115]
4-{[5-(4-Fluorophenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]n-
onane, [0116]
4-[(5-Pyridin-2-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e, [0117]
4-[(5-Pyridin-4-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.-
2.2]nonane, [0118]
4-[(5-Pyridin-3-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e, [0119]
5'-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1-methyl-1H,2'H-3,3-
'-bipyrazole, [0120]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole, [0121]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-8-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole, [0122]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole, [0123]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(4-fluorophenyl)-4,5-dihydr-
o-1H-indazole [0124]
4-(Isothiazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane [0125]
4-[(5-Bromoisothiazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
[0126]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5-dihydro-1H-benzo[g]indazo-
le [0127]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,5-dihydroisochrome-
no[4,3-c]pyrazole [0128]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5-dihydro-1H-pyrazolo[3,4-f-
]quinoline [0129]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-[(3S)-3-methoxypyrrolidin-1-
-yl]-1,4-dihydrochromeno[4,3-c]pyrazole [0130]
7-Bromo-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4-
,3-c]pyrazole, [0131]
3-(1,4-Dzabicyclo[3.2.2]non-4-ylcarbonyl)-1H-pyrazol-5-amine,
[0132] and tautomers thereof, and pharmaceutically acceptable salts
thereof (such as a hydrochloride salt), and
[0133] wherein if the compound exhibits chirality it can be in the
form of a mixture of enantiomers such as a racemate or a mixture of
diastereomers, or can be in the form of a single enantiomer or a
single diastereomer.
[0134] According to a further aspect, the invention relates to the
following compounds of Formula I: [0135]
4-[(4-Chloro-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
[0136]
4-[(4-nitro-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e, [0137]
4-[(5-Methyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]no-
nane, [0138]
4-(1H-pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane, [0139]
4-{[5-(4-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo-
[3.2.2]nonane, [0140]
4-[(5-Phenylisoxazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
[0141]
4-{[5-(2-thienyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonane-
, [0142]
4-[(5-Phenyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]non-
ane, [0143]
4-[(5-Cyclopropyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane-
, [0144]
4-{[5-(3-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicycl-
o[3.2.2]nonane, [0145]
4-(1,4,5,6-Tetrahydrocyclopenta[c]pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[-
3.2.2]nonane, [0146]
4-{[5-(2-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]-
nonane, [0147]
4-[(4-Bromo-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
[0148]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)isothiazol-4-amine,
[0149]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4,-
3-c]pyrazole, [0150]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5,6,7,8,9-hexahydro-1H-cycl-
oocta[c]pyrazole, [0151]
4-{[5-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-yl]carbonyl}-1,4-di-
azabicyclo[3.2.2]nonane, [0152]
4-{[5-(2-Naphthyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonan-
e, [0153]
4-{[5-(3-Thienyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2-
.2]nonane, [0154]
4-{[5-(4-Fluorophenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]n-
onane, [0155]
4-[(5-Pyridin-2-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e, [0156]
4-[(5-Pyridin-4-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.-
2.2]nonane, [0157]
4-[(5-Pyridin-3-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e, [0158]
5'-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1-methyl-1H,2'H-3,3-
'-bipyrazole, [0159]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole, [0160]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-8-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole, [0161]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole, [0162]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(4-fluorophenyl)-4,5-dihydr-
o-1H-indazole [0163]
4-(Isothiazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane [0164]
4-[(5-Bromoisothiazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
[0165]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5-dihydro-1H-benzo[g]indazo-
le [0166]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,5-dihydroisochrome-
no[4,3-c]pyrazole [0167]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5-dihydro-1H-pyrazolo[3,4-f-
]quinoline [0168]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-[(3S)-3-methoxypyrrolidin-1-
-yl]-1,4-dihydrochromeno[4,3-c]pyrazole [0169]
7-Bromo-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4-
,3-c]pyrazole, [0170] and tautomers thereof, and pharmaceutically
acceptable salts thereof (such as a hydrochloride salt), and
[0171] wherein if the compound exhibits chirality it can be in the
form of a mixture of enantiomers such as a racemate or a mixture of
diastereomers, or can be in the form of a single enantiomer or a
single diastereomer.
[0172] According to a further aspect, the invention relates to the
following compounds of Formula I: [0173]
4-[(4-Chloro-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
[0174]
4-[(4-nitro-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e, [0175]
4-[(5-Methyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]no-
nane, [0176]
4-(1H-pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane, [0177]
4-{[5-(4-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo-
[3.2.2]nonane, [0178]
4-[(5-Phenylisoxazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
[0179]
4-{[5-(2-thienyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonane-
, [0180]
4-[(5-Phenyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]non-
ane, [0181]
4-[(5-Cyclopropyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane-
, [0182]
4-{[5-(3-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicycl-
o[3.2.2]nonane, [0183]
4-(1,4,5,6-Tetrahydrocyclopenta[c]pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[-
3.2.2]nonane, [0184]
4-{[5-(2-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]-
nonane, [0185]
4-[(4-Bromo-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane,
[0186]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)isothiazol-4-amine,
[0187]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4,-
3-c]pyrazole, [0188]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5,6,7,8,9-hexahydro-1H-cycl-
oocta[c]pyrazole, [0189]
4-{[5-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-yl]carbonyl}-1,4-di-
azabicyclo[3.2.2]nonane, [0190]
4-{[5-(2-Naphthyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonan-
e, [0191]
4-{[5-(3-Thienyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2-
.2]nonane, [0192]
4-{[5-(4-Fluorophenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]n-
onane, [0193]
4-[(5-Pyridin-2-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e, [0194]
4-[(5-Pyridin-4-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.-
2.2]nonane, [0195]
4-[(5-Pyridin-3-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonan-
e, [0196]
5'-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1-methyl-1H,2'H-3,3-
'-bipyrazole, [0197]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole, [0198]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-8-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole, [0199]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-methoxy-1,4-dihydrochromeno-
[4,3-c]pyrazole, [0200] and tautomers thereof, and pharmaceutically
acceptable salts thereof (such as a hydrochloride salt), and
[0201] wherein if the compound exhibits chirality it can be in the
form of a mixture of enantiomers such as a racemate or a mixture of
diastereomers, or can be in the form of a single enantiomer or a
single diastereomer.
[0202] According to a further aspect, the invention relates to the
following compounds: [0203]
(1H-Pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane
hydrochloride, and [0204]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4,3-c]pyr-
azole hydrochloride,
[0205] wherein if the compound exhibits chirality it can be in the
form of a mixture of enantiomers such as a racemate or a mixture of
diastereomers, or can be in the form of a single enantiomer or a
single diastereomer.
Alternative Forms of Novel Compounds [63] Also included in the
compounds of the present invention are (a) the stereoisomers
thereof, (b) the pharmaceutically acceptable salts thereof, (c) the
tautomers thereof, (d) the protected acids and the conjugate acids
thereof, and (e) the prodrugs thereof.
[0206] One of ordinary skill in the art will recognize that
compounds of Formula I can exist in different geometrical isomeric
forms. Examples of geometric isomers include, but are not limited
to, cis isomers or trans isomers across a double bond. In addition,
some of the compounds of the present invention possess one or more
asymmetric atoms and are thus capable of existing in the form of
optical isomers, as well as in the form of racemic or nonracemic
mixtures thereof, and in the form of diastereomers and
diastereomeric mixtures inter alia. All of these compounds,
including cis isomers, trans isomers, diastereomic mixtures,
racemates, nonracemic mixtures of enantiomers, substantially pure,
and pure enantiomers, are within the scope of the present
invention. Substantially pure enantiomers contain no more than 5%
w/w of the corresponding opposite enantiomer, preferably no more
than 2%, most preferably no more than 1%.
[0207] The optical isomers can be obtained by resolution of the
racemic mixtures according to conventional processes, for example,
by the formation of diastereomeric salts using an optically active
acid or base or formation of covalent diastereomers.
[0208] Examples of appropriate acids are tartaric,
diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and
camphorsulfonic acid. Mixtures of diastereomers can be separated
into their individual diastereomers on the basis of their physical
and/or chemical differences by methods known to those skilled in
the art, for example, by chromatography or fractional
crystallization. The optically active bases or acids are then
liberated from the separated diastereomeric salts.
[0209] A different process for separation of optical isomers
involves the use of chiral chromatography (e.g., chiral HPLC
columns), with or without conventional derivation, optimally chosen
to maximize the separation of the enantiomers. Suitable chiral HPLC
columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel
OJ among many others, all routinely selectable. Enzymatic
separations, with or without derivitization, are also useful. The
optically active compounds of Formula I can likewise be obtained by
utilizing optically active starting materials in chiral syntheses
processes under reaction conditions which do not cause
racemization.
[0210] In addition, one of ordinary skill in the art will recognize
that the compounds can be used in different enriched isotopic
forms, e.g., enriched in the content of .sup.2H, .sup.3, .sup.11C,
.sup.13C and/or .sup.14C. In one particular embodiment, the
compounds are deuterated. Such deuterated forms can be made by the
procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. As
described in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration
can improve the efficacy and increase the duration of action of
drugs.
[0211] Deuterium substituted compounds can be synthesized using
various methods such as described in: Dean, Dennis C.; Editor.
Recent Advances in the Synthesis and Applications of Radiolabeled
Compounds for Drug Discovery and Development. [In: Curr., Pharm.
Des., 2000; 6(10)] (2000), 110 pp. CAN 133:68895 AN 2000:473538
CAPLUS; Kabalka, George W.; Varma, Rajender S. The Synthesis of
Radiolabeled Compounds via Organometallic Intermediates.
Tetrahedron (1989), 45(21), 6601-21, CODEN: TETRAB ISSN:0040-4020.
CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E. Anthony.
Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981),
64(1-2), 9-32. CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN
1981:476229 CAPLUS.
[0212] Pharmaceutically acceptable salts of the compounds of the
present invention include salts commonly used to form alkali metal
salts or form addition salts of free acids or free bases. The
nature of the salt is not critical, provided that it is
pharmaceutically-acceptable. Suitable pharmaceutically acceptable
acid addition salts may be prepared from an inorganic acid or from
an organic acid. Examples of such inorganic acids include, but are
not limited to, hydrochloric, hydrobromic, hydroiodic, nitric,
carbonic, sulfuric, and phosphoric acid. Appropriate organic acids
may be selected from aliphatic, cycloaliphatic, aromatic,
heterocyclic, carboxylic, and sulfonic classes of organic acids.
Examples of organic and sulfonic classes of organic acids includes,
but are not limited to, formic, acetic, propionic, succinic,
glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,
glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,
anthranilic, mesylic, salicylic, 4-hydroxybenzoic, phenylacetic,
mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,
benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic,
toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic,
algenic, N-hydroxybutyric, salicylic, galactaric, and galacturonic
acid, and combinations thereof.
[0213] Tautomers of the compounds of the invention are encompassed
by the present invention. Thus, for example, a carbonyl includes
its hydroxy tautomer. The protected acids include, but are not
limited to, esters, hydroxyamino derivatives, amides and
sulfonamides.
[0214] The present invention includes the prodrugs and salts of the
prodrugs.
[0215] Formation of prodrugs is well known in the art in order to
enhance the properties of the parent compound; such properties
include solubility, absorption, biostability, and release time
(see, e.g., "Pharmaceutical Dosage Form and Drug Delivery Systems"
(Sixth Edition), edited by Ansel et al., publ. by Williams &
Wilkins, pgs. 27-29, (1995), which is hereby incorporated by
reference). Commonly used prodrugs are designed to take advantage
of the major drug biotransformation reactions, and are also to be
considered within the scope of the invention. Major drug
biotransformation reactions include N-dealkylation, O-dealkylation,
aliphatic hydroxylation, aromatic hydroxylation, N-oxidation,
S-oxidation, deamination, hydrolysis reactions, glucuronidation,
sulfation, and acetylation (see, e.g., Goodman and Gilman's The
Pharmacological Basis of Therapeutics (Ninth Edition), editor
Molinoff et al., publ. by McGraw-Hill, pages 11-13, (1996), which
is hereby incorporated by reference).
[0216] Preferred aspects include pharmaceutical compositions
comprising a compound of this invention and a pharmaceutically
acceptable carrier and, optionally, another active agent as
discussed below; a method of stimulating, activating or inhibiting
alpha-7 nicotinic receptors, e.g., as determined by a conventional
assay or one described herein, either in vitro or in vivo (in an
animal, e.g., in an animal model, or in a mammal or in a human); a
method of treating a neurological syndrome, e.g., loss of memory,
especially long-term memory, cognitive impairment or decline,
memory impairment, etc.; and a method of treating a disease state
modulated by nicotinic alpha-7 activity, in a mammal, e.g., a
human, e.g., those mentioned herein.
General Preparative Methods
[0217] In general, the compounds used in this invention may be
prepared by standard techniques known in the art, by known
processes analogous thereto, and/or by the processes described
herein, using starting materials which are either commercially
available or producible according to routine, conventional chemical
methods. The following preparative methods are presented to aid the
reader in the synthesis of the compounds of the present
invention.
[0218] Additionally, sensitive or reactive groups on a compound of
Formula (I) may need to be protected and deprotected during any of
the above methods. Protecting groups in general may be added and
removed by conventional methods well known in the art (see, e.g.,
T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis; Wiley: New York, (1999)).
[0219] The particular process to be utilized in the preparation of
the compounds of this invention depends upon the specific compound
desired. Such factors as the selection of the specific moiety, and
the specific substituents possible at various locations on the
molecule, all play a role in the path to be followed in the
preparation of the specific compounds of this invention. Those
factors are readily recognized by one of ordinary skill in the
art.
[0220] The compounds of the present invention may be prepared
conventionally. Some of the known processes that can be used are
described below. All starting materials are known or can be
conventionally prepared from known starting materials.
[0221] The synthesis of similar compounds is disclosed in copending
application Ser. No. 11/123,219, filed May 6, 2005, which claims
the benefit of U.S. Provisional Application Ser. No. 60/568,696,
filed May 7, 2004, U.S. Provisional Application Ser. No.
60/574,712, filed May 27, 2004, and U.S. Provisional Application
Ser. No. 60/626,469, filed Nov. 10, 2004, the entire disclosures of
each of which are hereby incorporated by reference.
[0222] Acids for use in the preparation of the bicyclobase amides
are either commercially available, or prepared by straightforward
methods known to those skilled in the art.
[0223] The bicycloamine for use in the preparation of the
bicyclobase amides is commercially available (Olainfarm). The
bicyclobase amide can be prepared by the coupling reaction of acids
with the bicycloamine and HATU or HBTU in DMF. The couplings are
generally performed at room temperatures for 18-24 hours. The
resultant adducts are isolated and purified by standard techniques,
such as chromatography or recrystallization, practiced by those
skilled in the art.
[0224] Compounds of Formula (I) are most generally prepared by the
coupling reaction depicted in Reaction Scheme 1.
##STR00017##
In this scheme, a heterocyclic carboxylic acid of formula (II) is
coupled with a bicyclic amine of formula (III), facilitated by a
coupling reagent such as HATU and a base such as
diisopropylethylamine (DIEA) in a inert polar solvent such as DMF.
The carboxylic acids are commercially available or prepared by
methods known in the art.
[0225] For example, carboxylic acids of formula (IIa) in which
R.sup.1 and R.sup.2 is
##STR00018##
may be prepared by the route illustrated in Reaction Scheme 2.
##STR00019##
In this scheme, an optionally substituted phenol of formula A is
O-alkylated to give the phenoxyalkanoic acid of formula B, which in
turn, is cyclized to the chromanone of formula C using an acid
catalyst, such as polyphosphoric acid. The intermediate of formula
C is then acylated with ethyl oxalate and strong base to give the
ketoester of formula D, which upon treatment with hydrazine gives
the fused pyrazole ester of formula E. This ester is hydrolyzed to
the desired carboxylic acid under basic conditions to provide the
compound of formula (IIa).
[0226] The salts, e.g., hydrochlorides, of compounds of Formula (I)
may be prepared by addition of a non-aqueous. e.g., methanolic,
solution of an organic or inorganic acid (e.g., HCl,
CF.sub.3CO.sub.2H, etc.) to a solution of the Formula (I) compound
and separation of the crystalline salt that is formed. Addition of
a non-solvent, such as ether, facilitates the isolate of the
salt.
[0227] By using these above described methods, the compounds
Formula (I) of the invention may be prepared as shown in Table 1
below:
TABLE-US-00001 TABLE 1 Ex. No. Structure NAME 1 ##STR00020##
4-[(4-chloro-1H-pyrazol-3- yl)carbonyl]-1,4-
diazabicyclo[3.2.2]nonane 2 ##STR00021## 4-[(4-nitro-1H-pyrazol-3-
yl)carbonyl]-1,4- diazabicyclo[3.2.2]nonane 3 ##STR00022##
4[(5-methyl-1H-pyrazol-3- yl)carbonyl]-1,4-
diazabicyclo[3.2.2]nonane 4 ##STR00023##
4-(1H-pyrazol-3-ylcarbonyl)- 1,4-diazabicyclo[3.2.2]nonane 5
##STR00024## 4-{[5-(4-methoxyphenyl)-1H-
pyrazol-3-yl]carbonyl}-1,4- diazabicyclo[3.2.2]nonane 6
##STR00025## 4-[(5-phenylisoxazol-3- yl)carbonyl]-1 ,4-
diazabicyclo[3.2.2]nonane 7 ##STR00026##
4-{[5-(2-thienyl)-1H-pyrazol-3- yl]carbonyl}-1 ,4-
diazabicyclo[3.2.2]nonane 8 ##STR00027## 4-[(5-phenyl-1H-pyrazol-3-
yl)carbonyl]-1,4- diazabicyclo[3.2.2]nonane 9 ##STR00028##
4-[(5-cyclopropyl-1H-pyrazol-3- yl)carbonyl]-1,4-
diazabicyclo[3.2.2]nonane 10 ##STR00029##
4-{[5-(3-methoxyphenyl)-1H- pyrazol-3-yl]carbonyl}-1,4-
diazabicyclo[3.2.2]nonane 11 ##STR00030## 4-(1,4,5,6-
tetrahydrocyclopenta[c]pyrazol- 3-ylcarbonyl)-1,4-
diazabicyclo[3.2.2]nonane 12 ##STR00031##
4-{[5-(2-methoxyphenyl)-1H- pyrazol-3-yl]carbonyl}-1,4-
diazabicyclo[3.2.2]nonane 13 ##STR00032## 4-[(4-bromo-1H-pyrazol-3-
yl)carbonyl]-1,4- diazabicyclo[3.2.2]nonane 14 ##STR00033##
3-(1,4-diazabicyclo[3.2.2]non-4- ylcarbonyl)isothiazol-4-amine 15
##STR00034## 3-(1,4-diazabicyclo[3.2.2]non-4- ylcarbonyl)-1,4-
dihydrochromeno[4,3-c] pyrazoles 16 ##STR00035##
3-(1,4-diazabicyclo[3.2.2]non-4- ylcarbonyl)-4,5,6,7,8,9-
hexahydro-1H- cycloocta[c]pyrazoles 17 ##STR00036##
4-{[5-(2,3-dihydro-1,4- benzodioxin-6-yl)-1H-pyrazol-3-
yl]carbonyl}-1,4- diazabicyclo[3.2.2]nonane 18 ##STR00037##
4-{[5-(2-naphthyl)-1H-pyrazol-3- yl]carbonyl}-1,4-
diazabicyclo[3.2.2]nonane 19 ##STR00038##
4-{[5-(3-thienyl)-1H-pyrazol-3- yl]carbonyl}-1,4-
diazabicyclo[3.2.2]nonane 20 ##STR00039##
4-{[5-(4-fluorophenyl)-1H- pyrazol-3-yl]carbonyl}-1,4-
diazabicyclo[3.2.2]nonane 21 ##STR00040##
4-[(5-pyridin-2-yl-1H-pyrazol-3- yl)carbonyl]-1,4-
diazabicyclo[3.2.2]nonane 22 ##STR00041##
4-[(5-pyridin-4-yl-1H-pyrazol-3- yl)carbonyl]-1,4-
diazabicyclo[3.2.2]nonane 23 ##STR00042##
4-[(5-pyridin-3-yl-1H-pyrazol-3- yl)carbonyl]-1,4-
diazabicyclo[3.2.2]nonane 24 ##STR00043##
5'-(1,4-diazabicyclo[3.2.2]non- 4-ylcarbonyl)-1-methyl-1 H,2'H-
3,3'-bipyrazole 25 ##STR00044## 3-(1,4-diazabicyclo[3.2.2]non-4-
ylcarbonyl)-6-methoxy-1,4- dihydrochromeno[4,3- c]pyrazoles 26
##STR00045## 3-(1,4-diazabicyclo[3.2.2]non-4-
ylcarbonyl)-8-methoxy-1,4- dihydrochromeno[4,3- c]pyrazoles 27
##STR00046## 3-(1,4-diazabicyclo[3.2.2]non-4-
ylcarbonyl)-7-methoxy-1,4- dihydrochromeno[4,3- c]pyrazoles 28
##STR00047## (1H-pyrazol-3-ylcarbonyl)-1,4-
diazabicyclo[3.2.2]nonane hydrochloride 29 ##STR00048##
3-(1,4-diazabicyclo[3.2.2]non-4- ylcarbonyl)-1,4-
dihydrochromeno[4,3- c]pyrazole hydrochloride 30 ##STR00049##
3-(1,4-diazabicyclo[3.2.2]non-4- ylcarbonyl)-6-(4-fluorophenyl)-
4,5-dihydro-1H-indazole 31 ##STR00050##
4-(isothiazol-3-ylcarbonyl)-1,4- diazabicyclo[3.2.2]nonane 32
##STR00051## 4-[(5-bromoisothiazol-3- yl)carbonyl]-1,4-
diazabicyclo[3.2.2]nonane 33 ##STR00052##
3-(1,4-diazabicyclo[3.2.2]non-4- ylcarbonyl)-4,5-dihydro-1H-
benzo[g]indazole 34 ##STR00053## 3-(1,4-diazabicyclo[3.2.2]non-4-
ylcarbonyl)-1,5- dihydroisochromeno[4,3- c]pyrazoles 35
##STR00054## 3-(1,4-diazabicyclo[3.2.2]non-4-
ylcarbonyl)-4,5-dihydro-1H- pyrazolo[3,4-f]quinoline 36
##STR00055## 3-(1,4-diazabicyclo[3.2.2]non-4-
ylcarbonyl)-7-[(3S)-3- methoxypyrrolidin-1-yl]-1,4-
dihydrochromeno[4,3- c]pyrazoles 37 ##STR00056## 7-bromo-3-(1,4-
diazabicyclo[3.2.2]non-4- ylcarbonyl)-1,4- dihydrochromeno[4,3-
c]pyrazoles 38 ##STR00057## 3-(1,4-diazabicyclo[3.2.2]non-4-
ylcarbonyl)-1H-pyrazol-5-amine
Methods of Treatment
[0228] Agents that bind to nicotinic acetylcholine receptors have
been indicated as useful in the treatment and/or prophylaxis of
various diseases and conditions, particularly psychotic diseases,
neurodegenerative diseases involving a dysfunction of the
cholinergic system, and conditions of memory and/or cognition
impairment, including, for example, schizophrenia, anxiety, mania,
depression, manic depression [examples of psychotic disorders],
Tourette's syndrome, Parkinson's disease, Huntington's disease
[examples of neurodegenerative diseases], cognitive disorders (such
as Alzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral
Sclerosis, memory impairment, memory loss, cognition deficit,
attention deficit, Attention Deficit Hyperactivity Disorder), and
other uses such as treatment of nicotine addiction, inducing
smoking cessation, treating pain (i.e., analgesic use), providing
neuroprotection, and treating jetlag. See, e.g., WO 97/30998; WO
99/03850; WO 00142044; WO 01/36417; Holladay et al., J. Med. Chem.,
40:26, 4169-94 (1997);
[0229] Schmitt et al., Annual Reports Med. Chem., Chapter 5, 41-51
(2000); Stevens et al., Psychopharmatology, (1998) 136: 320-27; and
Shytle et al., Molecular Psychiatry, (2002), 7, pp. 525-535.
[0230] Thus, in accordance with the invention, there is provided a
method of treating a patient, especially a human, suffering from
psychotic diseases, neurodegenerative diseases involving a
dysfunction of the cholinergic system, and conditions of memory
and/or cognition impairment, including, for example, schizophrenia,
anxiety, mania, depression, manic depression [examples of psychotic
disorders], Tourette's syndrome, Parkinson's disease, Huntington's
disease [examples of neurodegenerative diseases], and/or cognitive
disorders (such as Alzheimer's disease, Lewy Body Dementia,
Amyotrophic Lateral Sclerosis, memory impairment, memory loss,
cognition deficit, attention deficit, Attention Deficit
Hyperactivity Disorder), comprising administering to the patient an
effective amount of a compound according to Formula I.
[0231] Neurodegenerative disorders included within the methods of
the present invention include, but are not limited to, treatment
and/or prophylaxis of Alzheimer's diseases, Pick's disease, diffuse
Lewy Body disease, progressive supranuclear palsy
[0232] (Steel-Richardson syndrome), multisystem degeneration
(Shy-Drager syndrome), motor neuron diseases including amyotrophic
lateral sclerosis (ALS), degenerative ataxias, cortical basal
degeneration, ALS-Parkinson's-Dementia complex of Guam, subacute
sclerosing panencephalitis, Huntington's disease, Parkinson's
disease, synucleinopathies, primary progressive aphasia,
striatonigral degeneration, Machado-Joseph disease/spinocerebellar
ataxia type 3, olivopontocerebellar degenerations, Gilles De La
Tourette's disease, bulbar palsy, pseudobulbar palsy, spinal
muscular atrophy, spinobulbar muscular atrophy (Kennedy's disease),
primary lateral sclerosis, familial spastic paraplegia,
Werdnig-Hoffmann disease, Kugelberg-Welander disease, Tay-Sach's
disease, Sandhoff disease, familial spastic disease,
Wohlfart-Kugelberg-Welander disease, spastic paraparesis,
progressive multifocal leukoencephalopathy, prion diseases (such as
Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease, Kuru and
fatal familial insomnia), and neurodegenerative disorders resulting
from cerebral ischemia or infarction including embolic occlusion
and thrombotic occlusion as well as intracranial hemorrhage of any
type (including, but not limited to, epidural, subdural,
subarachnoid and intracerebral), and intracranial and
intravertebral lesions (including, but not limited to, contusion,
penetration, shear, compression and laceration)
[0233] In addition, .alpha.7nACh receptor agonists, such as the
compounds of the present invention can be used to treat age-related
dementia and other dementias and conditions with memory loss
including age-related memory loss, senility, vascular dementia,
diffuse white matter disease (Binswanger's disease), dementia of
endocrine or metabolic origin, dementia of head trauma and diffuse
brain damage, dementia pugilistica and frontal lobe dementia. See,
e.g., WO 99162505. Thus, in accordance with the invention, there is
provided a method of treating a patient, especially a human,
suffering from age-related dementia and other dementias and
conditions with memory loss comprising administering to the patient
an effective amount of a compound according to Formula I.
[0234] Thus, in accordance with a further embodiment, the present
invention includes methods of treating patients suffering from
memory impairment due to, for example, Alzheimer's disease, mild
cognitive impairment due to aging, schizophrenia, Parkinson's
disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob
disease, depression, aging, head trauma, stroke, CNS hypoxia,
cerebral senility, multiinfarct dementia and other neurological
conditions, as well as HIV and cardiovascular diseases, comprising
administering an effective amount of a compound according to
Formula I.
[0235] Additionally, the present invention includes methods of
treating patients suffering from memory impairment as a result of,
for example, chemotherapy, kidney dialysis, post-operative surgery,
as well as memory impairment associated with bipolar disorders,
comprising administering an effective amount of a compound
according to Formula I.
[0236] Amyloid precursor protein (APP) and A.beta. peptides derived
therefrom, e.g., A.beta.1-40, A.beta.1-42, and other fragments, are
known to be involved in the pathology of Alzheimer's disease. The
A61-42 peptides are not only implicated in neurotoxicity but also
are known to inhibit cholinergic transmitter function. Further, it
has been determined that A.beta. peptides bind to .alpha.7nACh
receptors. Thus, agents which block the binding of the A.beta.
peptides to .alpha.-7 nAChRs are useful for treating
neurodegenerative diseases. See, e.g., WO 99/62505. In addition,
stimulation .alpha.7nACh receptors can protect neurons against
cytotoxicity associated with A.beta. peptides. See, e.g., Kihara,
T. et al., Ann. Neural., 1997, 42, 159.
[0237] Thus, in accordance with an embodiment of the invention
there is provided a method of treating and/or preventing dementia
in an Alzheimer's patient which comprises administering to the
subject a therapeutically effective amount of a compound according
to Formula Ito inhibit the binding of an amyloid beta peptide
(preferably, A.beta.1-42) with nACh receptors, preferable
.alpha.7nACh receptors, most preferably, human .alpha.7nACh
receptors (as well as a method for treating and/or preventing other
clinical manifestations of Alzheimer's disease that include, but
are not limited to, cognitive and language deficits, apraxias,
depression, delusions and other neuropsychiatric symptoms and
signs, and movement and gait abnormalities).
[0238] The present invention also provides methods for treating
other amyloidosis diseases, for example, hereditary cerebral
angiopathy, nonneuropathic hereditary amyloid, Down's syndrome,
macroglobulinemia, secondary familial Mediterranean fever,
Muckle-Wells syndrome, multiple myeloma, pancreatic- and
cardiac-related amyloidosis, chronic hemodialysis anthropathy, and
Finnish and Iowa amyloidosis.
[0239] In addition, nicotinic receptors have been implicated as
playing a role in the body's response to alcohol ingestion. Thus,
agonists for .alpha.7nACh receptors can be used in the treatment of
alcohol withdrawal and in anti-intoxication therapy. Thus, in
accordance with an embodiment of the invention there is provided a
method of treating a patient for alcohol withdrawal or treating a
patient with anti-intoxication therapy comprising administering to
the patient an effective amount of a compound according to Formula
I.
[0240] Agonists for the .alpha.7nACh receptor subtypes can also be
used for neuroprotection against damage associated with strokes and
ischemia and glutamate-induced excitotoxicity. Thus, in accordance
with an embodiment of the invention there is provided a method of
treating a patient to provide for neuroprotection against damage
associated with strokes and ischemia and glutamate-induced
excitotoxicity comprising administering to the patient an effective
amount of a compound according to Formula I.
[0241] As noted above, agonists for the .alpha.7nACh receptor
subtypes can also be used in the treatment of nicotine addiction,
inducing smoking cessation, treating pain, and treating jetlag,
obesity, diabetes, and inflammation. Thus, in accordance with an
embodiment of the invention there is provided a method of treating
a patient suffering from nicotine addiction, pain, jetlag, obesity
and/or diabetes, or a method of inducing smoking cessation in a
patient comprising administering to the patient an effective amount
of a compound according to Formula I.
[0242] The inflammatory reflex is an autonomic nervous system
response to an inflammatory signal. Upon sensing an inflammatory
stimulus, the autonomic nervous system responds through the vagus
nerve by releasing acetylcholine and activating nicotinic .alpha.7
receptors on macrophages. These macrophages in turn release
cytokines. Dysfunctions in this pathway have been linked to human
inflammatory diseases including rheumatoid arthritis, diabetes and
sepsis. Macrophages express the nicotinic .alpha.7 receptor and it
is likely this receptor that mediates the cholinergic
anti-inflammatory response. Therefore, compounds with affinity for
the .alpha.7nACh receptor on macrophages may be useful for human
inflammatory diseases including rheumatoid arthritis, diabetes and
sepsis. See, e.g., Czura, C J et al., J. Intern. Med., 2005,
257(2), 156-66.
[0243] Thus, in accordance with an embodiment of the invention
there is provided a method of treating a patient (e.g., a mammal,
such as a human) suffering from inflammation comprising
administering to the patient an effective amount of a compound
according to Formula I. Similarly, in accordance with another
embodiment of the invention there is provided a method of treating
a patient (e.g., a mammal, such as a human) suffering from an
inflammatory disease, such as, but not limited to, rheumatoid
arthritis, diabetes or sepsis, comprising administering to the
patient an effective amount of a compound according to Formula I.
In accordance with a further embodiment of the invention there is
provided a method of treating a patient (e.g., a mammal, such as a
human) suffering from inflammatory due to, for example, but not
limited to, an autoimmune disease, fibromyalgia, or ulcerative
colitis, comprising administering to the patient an effective
amount of a compound according to Formula I.
[0244] In addition, due to their affinity to .alpha.7nACh
receptors, labeled derivatives of the compounds of Formula I (e.g.,
C11 or F18 labeled derivatives), can be used in neuroimaging of the
receptors within, e.g., the brain. Thus, using such labeled agents
in vivo imaging of the receptors can be performed using, e.g., PET
imaging. The condition of memory impairment is manifested by
impairment of the ability to learn new information and/or the
inability to recall previously learned information. Memory
impairment is a primary symptom of dementia and can also be a
symptom associated with such diseases as Alzheimer's disease,
schizophrenia, Parkinson's disease, Huntington's disease, Pick's
disease, Creutzfeldt-Jakob disease, HIV, cardiovascular disease,
and head trauma as well as age-related cognitive decline.
[0245] Thus, in accordance with an embodiment of the invention
there is provided a method of treating a patient suffering from,
for example, mild cognitive impairment (MCI), vascular dementia
(VaD), age-associated cognitive decline (AACD), amnesia associated
w/open-heart-surgery, cardiac arrest, and/or general anesthesia,
memory deficits from early exposure of anesthetic agents, sleep
deprivation induced cognitive impairment, chronic fatigue syndrome,
narcolepsy, AIDS-related dementia, epilepsy-related cognitive
impairment, Down's syndrome, Alcoholism related dementia,
drug/substance induced memory impairments, Dementia Puglistica
(Boxer Syndrome), and animal dementia (e.g., dogs, cats, horses,
etc.) comprising administering to the patient an effective amount
of a compound according to Formula I.
[0246] The dosages of the compounds of the present invention depend
upon a variety of factors including the particular syndrome to be
treated, the severity of the symptoms, the route of administration,
the frequency of the dosage interval, the particular compound
utilized, the efficacy, toxicology profile, pharmacokinetic profile
of the compound, and the presence of any deleterious side-effects,
among other considerations.
[0247] The compounds of the invention can be administered to
patients, e.g., mammals, particularly humans, at typical dosage
levels customary for .alpha.-7 nicotinic receptor agonists such as
the known .alpha.-7 nicotinic receptor agonist compounds mentioned
above. For example, the compounds can be administered, in single or
multiple doses, by oral administration at a dosage level of, for
example, 0.0001-10 mg/kg/day, e.g., 0.01-10 mg/kg/day. Unit dosage
forms can contain, for example, 1-200 mg of active compound. For
intravenous administration, the compounds can be administered in
single or multiple dosages.
[0248] In carrying out the procedures of the present invention it
is of course to be understood that reference to particular buffers,
media, reagents, cells, culture conditions and the like are not
intended to be limiting, but are to be read so as to include all
related materials that one of ordinary skill in the art would
recognize as being of interest or value in the particular context
in which that discussion is presented. For example, it is often
possible to substitute one buffer system or culture medium for
another and still achieve similar, if not identical, results. Those
of skill in the art will have sufficient knowledge of such systems
and methodologies so as to be able, without undue experimentation,
to make such substitutions as will optimally serve their purposes
in using the methods and procedures disclosed herein.
[0249] The compounds of the invention also are useful as
intermediates for making other compounds of the inventive genus.
Thus, for example, compounds exhibiting relatively low activity are
also useful for preparing other compounds within the inventive
genus.
[0250] A compound of Formula (I) can be administered as the sole
active agent or in combination with other pharmaceutical agents
such as other agents used in the treatment of cognitive impairment
and/or memory loss, e.g., other .alpha.-7 agonists, PDE4
inhibitors, calcium channel blockers, muscarinic m1 and m2
modulators, adenosine receptor modulators, ampakines, NMDA-R
modulators, mGluR modulators, dopamine modulators, serotonin
modulators, cannabinoid modulators, cholinesterase inhibitors
(e.g., donepezil, rivastigimine, and galanthamine), agents for the
treatment of ADHD, anti-depressants, anti-inflammatory agents,
anti-psychotic agents (e.g., PDE10 inhibitors), beta secretase
modulators, bipolar disorder agents, GABA-nergic drugs, gamma
secretase modulators, histamine H3, kinase inhibitors, MAO-B
inhibitors, mood stabilizers, 5HT4 modulating agents, 5HT6
antagonists, and .alpha.4.beta.2 modulating agents. In such
combinations, each active ingredient can be administered either in
accordance with their usual dosage range or a dose below their
usual dosage range.
[0251] The compounds of the invention can be used in conjunction
with "positive modulators" which enhance the efficacy of nicotinic
receptor agonists. See, e.g., the positive modulators disclosed in
WO 99/56745, WO 01/32619, and WO 01/32622. Such combinational
therapy can be used in treating conditions/diseases associated with
reduced nicotinic transmission.
[0252] Further the compounds may be used in conjunction with
compounds that bind to A.beta. peptides and thereby inhibit the
binding of the peptides to .alpha.7nAChr subtypes. See, e.g., WO
99/62505.
[0253] The present invention further includes methods of treatment
that involve activation of .alpha.-7 nicotinic receptors. Thus, the
present invention includes methods of selectively
activating/stimulating .alpha.-7 nicotinic receptors in a patient
(e.g., a mammal such as a human) wherein such
activation/stimulation has a therapeutic effect, such as where such
activation may relieve conditions involving neurological syndromes,
such as the loss of memory, especially long-term memory. Such
methods comprise administering to a patient (e.g., a mammal such as
a human), an effective amount of a compound of Formula I alone or
as part of a formulation, as disclosed herein. Such co-therapies
may be administered in any combination of two or more drugs Such
co-therapies may be administered in the form of pharmaceutical
compositions, as described below.
Pharmaceutical Compositions
[0254] As used herein, various terms are defined below. When
introducing elements of the present invention or the preferred
embodiment(s) thereof, the articles "a," "an," "the," and "said"
are intended to mean that there are one or more of the elements.
The terms "comprising," "including," and "having" are intended to
be inclusive and mean that there may be additional elements other
than the listed elements.
[0255] The term "subject" as used herein includes mammals (e.g.,
humans and animals).
[0256] The term "treatment" includes any process, action,
application, therapy, or the like, wherein a subject, including a
human being, is provided medical aid with the object of improving
the subject's condition, directly or indirectly, or slowing the
progression of a condition or disorder in the subject.
[0257] The term "combination therapy" or "co-therapy" means the
administration of two or more therapeutic agents to treat a
condition and/or disorder. Such administration encompasses
co-administration of two or more therapeutic agents in a
substantially simultaneous manner, such as in a single capsule
having a fixed ratio of active ingredients or in multiple, separate
capsules for each inhibitor agent. In addition, such administration
encompasses use of each type of therapeutic agent in a sequential
manner. Additionally, each therapeutic agent may be administered
using the same or different modes of administration.
[0258] The phrase "therapeutically effective" means the amount of
each agent administered that will achieve the goal of improvement
in conditions or severity of disorders associated with defective or
malfunctioning nicotinic acetylcholine receptors, while avoiding or
minimizing adverse side effects associated with the given
therapeutic treatment.
[0259] The term "pharmaceutically acceptable" means that the
subject item is appropriate for use in a pharmaceutical
product.
[0260] Based on well known assays used to determine the efficacy
for treatment of conditions identified above in mammals, and by
comparison of these results with the results of known medicaments
that are used to treat these conditions, the effective dosage of
Formula (I) compounds(s) can readily be determined for treatment of
each desired indication. The amount of the active ingredient (e.g.,
a compound of Formula (I)) to be administered in the treatment of
one of these conditions can vary widely according to such
considerations as the particular compound and dosage unit employed,
the mode of administration, the period of treatment, the age and
sex of the patient treated, and the nature and extent of the
condition treated.
[0261] Formula (I) compounds for use in methods of the invention
may be administered as compound per se. Alternatively, a compound
of Formula (I) may be administered with an acceptable carrier in
the form of a pharmaceutical composition. The pharmaceutically
acceptable carrier must be compatible with the other ingredients of
the composition and must not be intolerably deleterious to the
recipient. The carrier can be a solid or a liquid, or both, and
preferably is formulated with the compound as a unit-dose
composition, for example, a tablet, which can contain from about
0.05% to about 95% by weight of the active compound(s) based on a
total weight of the dosage form. Other pharmacologically active
substances can also be present, including other compounds useful in
the treatment of a condition associated with defective or
malfunctioning nicotinic acetylcholine receptors.
[0262] A compound of Formula (I) for use in methods of the present
invention may be administered by any suitable route, preferably in
the form of a pharmaceutical composition adapted to such a route,
and in a therapeutically effective dose for the treatment intended.
A compound of Formula (I) may, for example, be administered orally,
sublingually, nasally, pulmonary, mucosally, parenterally,
intravascularly, intraperitoneally, subcutaneously, intramuscularly
or topically. Unit dose formulations, particularly orally
administrable unit dose formulations such as tablets or capsules,
generally contain, for example, from about 0.001 to about 500 mg,
preferably from about 0.005 mg to about 100 mg, and more preferably
from about 0.01 to about 50 mg, of the active ingredient. In the
case of pharmaceutically acceptable salts, the weights indicated
above for the active ingredient refer to the weight of the
pharmaceutically active ion derived from the salt.
[0263] Of course, the specific initial and continuing dosage
regimen to prevent, treat, give relief from, or ameliorate a
condition or disorder associated with defective or malfunctioning
nicotinic acetylcholine receptors, or to otherwise protect against
or treat these conditions for each patient will vary according to
the nature and severity of the condition as determined by the
attending diagnostician, the activity of the specific Formula (I)
compound employed, the age of the patient, the diet of the patient,
time of administration, route of administration, rate of excretion
of the drug, drug combinations, pharmacological considerations such
as the activity, efficacy, pharmacokinetics and toxicology profiles
of the particular Formula (I) inhibitor employed, whether a drug
delivery system is utilized, and whether the Formula (I) compound
is administered with other active ingredients, and the like. The
desired mode of treatment and number of doses of an .alpha.7nAChR
inhibitor may be ascertained by those skilled in the art using
conventional treatment tests.
[0264] The Formula (I) compound may be utilized to achieve the
desired pharmacological effect by administration to a patient in
need thereof in an appropriately formulated pharmaceutical
composition. A patient, for the purpose of this invention, is a
mammal, including a human, in need of treatment for a particular
condition or disease. Therefore, the present invention includes
pharmaceutical compositions which are comprised of a
pharmaceutically acceptable carrier and a therapeutically effective
amount of the Formula (I) compound. A pharmaceutically acceptable
carrier is any carrier which is relatively non-toxic and innocuous
to a patient at concentrations consistent with effective activity
of the active ingredient so that any side effects ascribable to the
carrier do not vitiate the beneficial effects of the active
ingredient. The Formula (I) compound may be administered with a
pharmaceutically acceptable carrier using any effective
conventional dosage unit forms, including, for example, immediate
and timed release preparations, orally, parenterally, topically, or
the like.
[0265] For oral administration, the Formula (I) compound may be
formulated into solid or liquid preparations such as, for example,
capsules, pills, tablets, troches, lozenges, melts, powders,
solutions, pastes, syrups, suspensions, or emulsions, and may be
prepared according to methods known to the art for the manufacture
of pharmaceutical compositions. The solid unit dosage forms may be
a capsule which can be of the ordinary hard- or soft-shelled
gelatin type containing, for example, surfactants, lubricants, and
inert fillers such as lactose, sucrose, calcium phosphate, and corn
starch. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient.
[0266] The Formula (I) compound may be tableted with conventional
tablet bases such as lactose, sucrose, and cornstarch in
combination with binders such as acacia, cornstarch, or gelatin;
disintegrating agents intended to assist the break-up and
dissolution of the tablet following administration such as potato
starch, alginic acid, corn starch, and guar gum; lubricants
intended to improve the flow of tablet granulation and to prevent
the adhesion of tablet material to the surfaces of the tablet dies
and punches, for example, talc, stearic acid, or magnesium, calcium
or zinc stearate; dyes; coloring agents; and flavoring agents
intended to enhance the aesthetic qualities of the tablets and make
them more acceptable to the patient. Suitable excipients for use in
oral liquid dosage forms include diluents such as water and
alcohols, for example, ethanol, benzyl alcohol, and polyethylene
alcohols, either with or without the addition of a pharmaceutically
acceptable surfactant, suspending agent, or emulsifying agent.
Various other materials may be present as coatings or to otherwise
modify the physical form of the dosage unit. For instance tablets,
pills or capsules may be coated with shellac, sugar or both.
[0267] Dispersible powders and granules are suitable for the
preparation of an aqueous suspension. They provide the active
ingredient in admixture with a dispersing or wetting agent, a
suspending agent, and one or more preservatives. Suitable
dispersing or wetting agents and suspending agents are exemplified
by those already mentioned above. Additional excipients, for
example, those sweetening, flavoring and coloring agents described
above, may also be present.
[0268] The pharmaceutical compositions of this invention may also
be in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil such as liquid paraffin or a mixture of vegetable
oils. Suitable emulsifying agents may be (1) naturally occurring
gums such as gum acacia and gum tragacanth, (2) naturally occurring
phosphatides such as soy bean and lecithin, (3) esters or partial
esters derived from fatty acids and hexitol anhydrides, for
example, sorbitan monooleate, and (4) condensation products of said
partial esters with ethylene oxide, for example, polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening and
flavoring agents.
[0269] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil such as, for example, arachis oil,
olive oil, sesame oil, or coconut oil; or in a mineral oil such as
liquid paraffin. The oily suspensions may contain a thickening
agent such as, for example, beeswax, hard paraffin, or cetyl
alcohol. The suspensions may also contain one or more
preservatives, for example, ethyl or n-propyl p-hydroxybenzoate;
one or more coloring agents; one or more flavoring agents; and/or
one or more sweetening agents such as sucrose or saccharin.
[0270] Syrups and elixirs may be formulated with sweetening agents
such as, for example, glycerol, propylene glycol, sorbitol, or
sucrose. Such formulations may also contain a demulcent, and
preservative, flavoring and coloring agents. Oral delivery of the
Formula (I) compound(s) can include formulations well known in the
art to provide immediate delivery or prolonged or sustained
delivery of a drug to the gastrointestinal tract by any number of
mechanisms. Immediate delivery formulations include, but are not
limited to, oral solutions, oral suspensions, fast-dissolving
tablets or capsules, sublingual tablets, disintegrating tablets and
the like. Prolonged or sustained delivery formulations include, but
are not limited to, pH sensitive release of the active ingredient
from the dosage form based on the changing pH of the small
intestine, slow erosion of a tablet or capsule, retention in the
stomach based on the physical properties of the formulation,
bioadhesion of the dosage form to the mucosal lining of the
intestinal tract, or enzymatic release of the active drug from the
dosage form. The intended effect is to extend the time period over
which an active drug molecule is delivered to the site of action by
manipulation of the dosage forma Thus, enteric-coated and
enteric-coated controlled release formulations may be used in
methods of the present invention. Suitable enteric coatings include
cellulose acetate phthalate, polyvinylacetate phthalate,
hydroxypropylmethyl-cellulose phthalate and anionic polymers of
methacrylic acid and methacrylic acid methyl ester.
[0271] Pharmaceutical compositions can be prepared by any suitable
method of pharmacy, which includes the step of bringing into
association, the Formula (I) compound and the carrier (which can
constitute one or more accessory ingredients). In general, the
compositions are prepared by uniformly and intimately admixing the
Formula (I) compound with a liquid or finely divided solid carrier,
or both, and then, if necessary, shaping the product. For example,
a tablet can be prepared by compressing or molding a powder or
granules of the inhibitors, optionally with one or more accessory
ingredients. Compressed tablets can be prepared by compressing, in
a suitable machine, the compound in a free-flowing form, such as a
powder or granules optionally mixed with a binder, lubricant, inert
diluent and/or surface active/dispersing agent(s). Molded tablets
can be made, for example, by molding the powdered compound in a
suitable machine.
[0272] Liquid dosage forms for oral administration can include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs containing inert diluents commonly used in the
art, such as water. Such compositions may also comprise adjuvants,
such as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring, and perfuming agents.
[0273] Pharmaceutical compositions suitable for buccal
(sub-lingual) administration include lozenges comprising a Formula
(I) compound in a flavored base, usually sucrose, and acacia or
tragacanth, and pastilles comprising the inhibitors in an inert
base such as gelatin and glycerin or sucrose and acacia.
[0274] The Formula (I) compound(s) may also be administered.
parenterally, that is, subcutaneously, intravenously,
intramuscularly, or interperitoneally, as injectable dosages of the
compound in a physiologically acceptable diluent with a
pharmaceutical carrier which may be a sterile liquid or mixture of
liquids such as water, saline, aqueous dextrose and related sugar
solutions; an alcohol such as ethanol, isopropanol, or hexadecyl
alcohol; glycols such as propylene glycol or polyethylene glycol;
glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol,
ethers such as poly(ethyleneglycol) 400; an oil; a fatty acid; a
fatty acid ester or glyceride; or an acetylated fatty acid
glyceride with or without the addition of a pharmaceutically
acceptable surfactant such as a soap or a detergent, suspending
agent such as pectin, carbomers, methycellulose,
hydroxypropylmethylcellulose, or carboxymethylcellulose, or
emulsifying agent and other pharmaceutical adjuvants.
[0275] Illustrative of oils which can be used in the parenteral
formulations of this invention are those of petroleum, animal,
vegetable, or synthetic origin, for example, peanut oil, soybean
oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum,
and mineral oil. Suitable fatty acids include oleic acid, stearic
acid, and isostearic acid. Suitable fatty acid esters are, for
example, ethyl oleate and isopropyl myristate. Suitable soaps
include fatty alkali metal, ammonium, and triethanolamine salts and
suitable detergents include cationic detergents, for example,
dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and
alkylamine acetates; anionic detergents, for example, alkyl, aryl,
and olefin sulfonates, alkyl, olefin, ether, and monoglyceride
sulfates, and sulfosuccinates; nonionic detergents, for example,
fatty amine oxides, fatty acid alkanolamides, and
polyoxyethylenepolypropylene copolymers; and amphoteric detergents,
for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline
quarternary ammonium salts, as well as mixtures.
[0276] The parenteral compositions of this invention may typically
contain from about 0.5% to about 25% by weight of the active
ingredient in solution. Preservatives and buffers may also be used
advantageously. In order to minimize or eliminate irritation at the
site of injection, such compositions may contain a non-ionic
surfactant having a hydrophile-lipophile balance (HLB) of from
about 12 to about 17. The quantity of surfactant in such
formulation ranges from about 5% to about 15% by weight. The
surfactant can be a single component having the above HLB or can be
a mixture of two or more components having the desired HLB.
[0277] Illustrative of surfactants used in parenteral formulations
are the class of polyethylene sorbitan fatty acid esters, for
example, sorbitan monooleate and the high molecular weight adducts
of ethylene oxide with a hydrophobic base, formed by the
condensation of propylene oxide with propylene glycol.
[0278] The pharmaceutical compositions may be in the form of
sterile injectable aqueous suspensions. Such suspensions may be
formulated according to known methods using suitable dispersing or
wetting agents and suspending agents such as, for example, sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents which may be a naturally occurring phosphatide such
as lecithin, a condensation product of an alkylene oxide with a
fatty acid, for example, polyoxyethylene stearate, a condensation
product of ethylene oxide with a long chain aliphatic alcohol, for
example, heptadecaethyleneoxycetanol, a condensation product of
ethylene oxide with a partial ester derived form a fatty acid and a
hexitol such as polyoxyethylene sorbitol monooleate, or a
condensation product of an ethylene oxide with a partial ester
derived from a fatty acid and a hexitol anhydride, for example
polyoxyethylene sorbitan monooleate.
[0279] The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent. Diluents and solvents that may be
employed are, for example, water, Ringer's solution, and isotonic
sodium chloride solution. In addition, sterile fixed oils are
conventionally employed as solvents or suspending media. For this
purpose, any bland, fixed oil may be employed including synthetic
mono or diglycerides. In addition, fatty acids such as oleic acid
may be used in the preparation of injectables.
[0280] A composition of the invention may also be administered in
the form of suppositories for rectal administration of the drug.
These compositions may be prepared by mixing the drug (e.g., the
Formula (I) compound) with a suitable non-irritation excipient
which is solid at ordinary temperatures but liquid at the rectal
temperature and will therefore melt in the rectum to release the
drug. Such materials are, for example, cocoa butter and
polyethylene glycol.
[0281] Another formulation employed in the methods of the present
invention employs transdermal delivery devices ("patches"). Such
transdermal patches may be used to provide continuous or
discontinuous infusion of the compounds of the present invention in
controlled amounts. The construction and use of transdermal patches
for the delivery of pharmaceutical agents is well known in the art
(see, e.g., U.S. Pat. No. 5,023,252, incorporated herein by
reference). Such patches may be constructed for continuous,
pulsatile, or on demand delivery of pharmaceutical agents.
[0282] It may be desirable or necessary to introduce the
pharmaceutical composition to the patient via a mechanical delivery
device. The construction and use of mechanical delivery devices for
the delivery of pharmaceutical agents is well known in the art. For
example, direct techniques for administering a drug directly to the
brain usually involve placement of a drug delivery catheter into
the patient's ventricular system to bypass the blood-brain barrier.
One such implantable delivery system, used for the transport of
agents to specific anatomical regions of the body, is described in
U.S. Pat. No. 5,011,472, incorporated herein by reference.
[0283] As noted above, a compound of Formula (I) can be
administered as the sole active agent or in combination with other
pharmaceutical agents. Thus, the pharmaceutical compositions
according to the invention may further comprise at least additional
active agent, such as other agents used in the treatment of
cognitive impairment and/or memory loss, e.g., other .alpha.-7
agonists, PDE4 inhibitors, calcium channel blockers, muscarinic m1
and m2 modulators, adenosine receptor modulators, ampakines, NMDA-R
modulators, mGluR modulators, dopamine modulators, serotonin
modulators, cannabinoid modulators, cholinesterase inhibitors
(e.g., donepezil, rivastigimine, and galanthamine), agents for the
treatment of ADHD, anti-depressants, anti-inflammatory agents,
anti-psychotic agents (e.g., PDE10 inhibitors), beta secretase
modulators, bipolar disorder agents, GABA-nergic drugs, gamma
secretase modulators, histamine H3, kinase inhibitors, MAO-B
inhibitors, mood stabilizers, 5HT4 modulating agents, 5HT6
antagonists, and .alpha.4.beta.2 modulating agents. In such
combinations, each active ingredient can be administered either in
accordance with their usual dosage range or a dose below their
usual dosage range.
[0284] The pharmaceutical composition according to the invention
may further comprise at least one "positive modulator" which
enhances the efficacy of nicotinic receptor agonists. See, e.g.,
the positive modulators disclosed in WO 99156745, WO 01/32619, and
WO 01/32622. Such combinational therapy can be used in treating
conditions/diseases associated with reduced nicotinic
transmission.
[0285] The pharmaceutical composition according to the invention
may further comprise at least one compound that binds to A.beta.
peptides and thereby inhibit the binding of the peptides to
.alpha.7nAChr subtypes. See, e.g., WO 99/62505.
[0286] The compositions of the invention may also contain other
conventional pharmaceutically acceptable compounding ingredients,
generally referred to as carriers or diluents, as necessary or
desired. Any of the compositions of this invention may be preserved
by the addition of an antioxidant such as ascorbic acid or by other
suitable preservatives. Conventional procedures for preparing such
compositions in appropriate dosage forms can be utilized.
[0287] Commonly used pharmaceutical ingredients which may be used
as appropriate to formulate the composition for its intended route
of administration include: acidifying agents, for example, but are
not limited to, acetic acid, citric acid, fumaric acid,
hydrochloric acid, nitric acid; and alkalinizing agents such as,
but are not limited to, ammonia solution, ammonium carbonate,
diethanolamine, monoethanolamine, potassium hydroxide, sodium
borate, sodium carbonate, sodium hydroxide, triethanolamine,
trolamine.
[0288] Other pharmaceutical ingredients include, for example, but
are not limited to, adsorbents (e.g., powdered cellulose and
activated charcoal); aerosol propellants (e.g., carbon dioxide,
CCl.sub.2F.sub.2, F.sub.2ClC--CClF.sub.2 and CClF.sub.3); air
displacement agents (e.g., nitrogen and argon); antifungal
preservatives (e.g., benzoic acid, butylparaben, ethylparaben,
methylparaben, propylparaben, sodium benzoate); antimicrobial
preservatives (e.g., benzalkonium chloride, benzethonium chloride,
benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol,
phenylethyl alcohol, phenylmercuric nitrate and thimerosal);
antioxidants (e.g., ascorbic acid, ascorbyl palmitate, butylated
hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid,
monothioglycerol, propyl gallate, sodium ascorbate, sodium
bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);
binding materials (e.g., block polymers, natural and synthetic
rubber, polyacrylates, polyurethanes, silicones and
styrene-butadiene copolymers); buffering agents (e.g., potassium
metaphosphate, potassium phosphate monobasic, sodium acetate,
sodium citrate anhydrous and sodium citrate dihydrate); carrying
agents (e.g., acacia syrup, aromatic syrup, aromatic elixir, cherry
syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil,
peanut oil, sesame oil, bacteriostatic sodium chloride injection
and bacteriostatic water for injection); chelating agents (e.g.,
edetate disodium and edetic acid); colorants (e.g., FD&C Red
No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue
No. 2, D&C Green No. 5, D&C Orange. No. 5, D&C Red No.
8, caramel and ferric oxide red); clarifying agents (e.g.,
bentonite); emulsifying agents (but are not limited to, acacia,
cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin,
sorbitan monooleate, polyethylene 50 stearate); encapsulating
agents (e.g., gelatin and cellulose acetate phthalate); flavorants
(e.g., anise oil, cinnamon oil, cocoa, menthol, orange oil,
peppermint oil and vanillin); humectants (e.g., glycerin, propylene
glycol and sorbitol); levigating agents (e.g., mineral oil and
glycerin); oils (e.g., arachis oil, mineral oil, olive oil, peanut
oil, sesame oil and vegetable oil); ointment bases (e.g., lanolin,
hydrophilic ointment, polyethylene glycol ointment, petrolatum,
hydrophilic petrolatum, white ointment, yellow ointment, and rose
water ointment); penetration enhancers (transdermal delivery)
(e.g., monohydroxy or polyhydroxy alcohols, saturated or
unsaturated fatty alcohols, saturated or unsaturated fatty esters,
saturated or unsaturated dicarboxylic acids, essential oils,
phosphatidyl derivatives, cephalin, terpenes, amides, ethers,
ketones and ureas); plasticizers (e.g., diethyl phthalate and
glycerin); solvents (e.g., alcohol, corn oil, cottonseed oil,
glycerin, isopropyl alcohol, mineral oil, oleic acid, peanut oil,
purified water, water for injection, sterile water for injection
and sterile water for irrigation); stiffening agents (e.g., cetyl
alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl
alcohol, white wax and yellow wax); suppository bases (e.g., cocoa
butter and polyethylene glycols (mixtures)); surfactants (e.g.,
benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80,
sodium lauryl sulfate and sorbitan monopalmitate); suspending
agents (e.g., agar, bentonite, carbomers, carboxymethylcellulose
sodium, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth
and veegum); sweetening e.g., aspartame, dextrose, glycerin,
mannitol, propylene glycol, saccharin sodium, sorbitol and
sucrose); tablet anti-adherents (e.g., magnesium stearate and
talc); tablet binders (e.g., acacia, alginic acid,
carboxymethylcellulose sodium, compressible sugar, ethylcellulose,
gelatin, liquid glucose, methylcellulose, povidone and
pregelatinized starch); tablet and capsule diluents (e.g., dibasic
calcium phosphate, kaolin, lactose, mannitol, microcrystalline
cellulose, powdered cellulose, precipitated calcium carbonate,
sodium carbonate, sodium phosphate, sorbitol and starch); tablet
coating agents (e.g., liquid glucose, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose, ethylcellulose, cellulose acetate phthalate and
shellac); tablet direct compression excipients (e.g., dibasic
calcium phosphate); tablet disintegrants (e.g., alginic acid,
carboxymethylcellulose calcium, microcrystalline cellulose,
polacrillin potassium, sodium alginate, sodium starch glycollate
and starch); tablet glidants (e.g., colloidal silica, corn starch
and talc); tablet lubricants (e.g., calcium stearate, magnesium
stearate, mineral oil, stearic acid and zinc stearate);
tablet/capsule opaquants (e.g., titanium dioxide); tablet polishing
agents (e.g., carnuba wax and white wax); thickening agents (e.g.,
beeswax, cetyl alcohol and paraffin); tonicity agents (e.g.,
dextrose and sodium chloride); viscosity increasing agents (e.g.,
alginic acid, bentonite, carbomers, carboxymethylcellulose sodium,
methylcellulose, povidone, sodium alginate and tragacanth); and
wetting agents (e.g., heptadecaethylene oxycetanol, lecithins,
polyethylene sorbitol monooleate, polyoxyethylene sorbitol
monooleate, and polyoxyethylene stearate).
[0289] The total daily dose of each inhibitor can be administered
to the patient in a single dose, or in multiple subdoses.
Typically, subdoses can be administered two to six times per day,
preferably two to four times per day, and even more preferably two
to three times per day. Doses can be in immediate release form or
sustained release form sufficiently effective to obtain the desired
control over the condition associated with defective or
malfunctioning nicotinic acetylcholine receptors.
[0290] Formula (I) compound(s) may also be utilized in
compositions, in research and diagnostics, or as analytical
reference standards, and the like. Therefore, the present invention
includes compositions which are comprised of an inert carrier and
an effective amount of the Formula (I) compound. An inert carrier
is any material which does not interact with a compound to be
carried and which lends support, means of conveyance, bulk,
traceable material, and the like to the compound to be carried. An
effective amount of compound is that amount which produces a result
or exerts an influence on the particular procedure being
performed.
[0291] A Formula (I) compound for use in methods of the invention
may also be administered as the pharmaceutically acceptable salt,
protected acid, conjugate acid, tautomer, prodrug or stereoisomer
of a compound found to have .alpha.7nAChR stimulating, activating
or inhibiting activity. Tautomers include, for example, hydroxy
tautomers. Protected acids include, but are not limited to,
protected acids such as esters, hydroxyamino derivatives, amides
and sulfonamides. Formation of prodrugs is well known in the art in
order to enhance the properties of the parent compound; such
properties include solubility, absorption, biostability and release
time (see "Pharmaceutical Dosage Form and Drug Delivery Systems"
(Sixth Edition), edited by. Ansel et al., publ. by Williams &
Wilkins, pgs. 27-29, (1995) which is hereby incorporated by
reference). Commonly used prodrugs are designed to take advantage
of the major drug biotransformation reactions and are also to be
considered within the scope of the invention. Major drug
biotransformation reactions include N-dealkylation, O-dealkylation,
aliphatic hydroxylation, aromatic hydroxylation, N-oxidation,
S-oxidation, deamination, hydrolysis reactions, glucuronidation,
sulfation and acetylation (see Goodman and Gilman's The
Pharmacological Basis of Therapeutics (Ninth Edition), editor
Molinoff et al., publ. by McGraw-Hill, pages 11-13, (1996), which
is hereby incorporated by reference).
[0292] Besides being useful for human treatment, administration of
a Formula (I) compound may also be useful for veterinary treatments
of companion animals (e.g., horses, dogs, cats, etc.), exotic
animals and farm animals. Even though the invention is described in
terms of human biology, it is understood by those of ordinary skill
in the art that the present invention is applicable to other
mammals as well.
[0293] Formulations suitable for subcutaneous, intravenous,
intramuscular, and the like; suitable pharmaceutical carriers; and
techniques for formulation and administration may be prepared by
any of the methods well known in the art (see, e.g., Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.,
20.sup.th edition, 2000).
[0294] The present invention will now be further described by way
of the following non-limiting examples. In applying the disclosure
of these examples, it should be kept clearly in mind that other and
different embodiments of the methods disclosed according to the
present invention will no doubt suggest themselves to those of
skill in the relevant art.
[0295] In the foregoing and in the following examples, all
temperatures are set forth uncorrected in degrees Celsius; and,
unless otherwise indicated, all parts and percentages are by
weight.
[0296] The entire disclosures of all applications, patents and
publications, cited above and below, are hereby incorporated by
reference.
Abbreviations and Acronyms
[0297] A comprehensive list of the abbreviations utilized by
organic chemists of ordinary skill in the art appears in the first
issue of each volume of the Journal of Organic Chemistry; this list
is typically presented in a table entitled Standard List of
Abbreviations. The abbreviations contained in said list, and all
abbreviations utilized by organic chemists of ordinary skill in the
art are hereby incorporated by reference. For purposes of this
invention, the chemical elements are identified in accordance with
the Periodic Table of the Elements, CAS version, Handbook of
Chemistry and Physics, 67th Ed., 1986-87.
[0298] More specifically, when the following abbreviations are used
throughout this disclosure, they have the following meaning: [0299]
Ac acetyl [0300] AcOH acetic acid
[0301] AIBN azobisisobutyronitrile [0302] amu atomic mass unit
[0303] aq aqueous [0304] Bu butyl [0305] CDI carbonyl diimidazole
[0306] Celite.RTM. brand of diatomaceous earth filtering agent,
registered trademark of Celite Corporation [0307] conc concentrated
[0308] d doublet [0309] doublet of doublet [0310] ddd doublet of
doublet of doublet [0311] DIBAL diisobutylaluminum hydride [0312]
DIPA diisopropylamine [0313] DME dimethyoxyethane [0314]
N,N-dimethyl formamide [0315] DMSO dimethylsulfoxide [0316]
DMSO-d.sub.6 dimethylsulfoxide-d.sub.6 [0317] dppf
1,1'-bis(diphenylphosphino)ferrocene [0318] EDCI
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [0319]
electron impact ionization [0320] EI-MS electron impact-mass
spectrometry [0321] equiv equivalent [0322] ES MS electrospray mass
spectrometry [0323] Et ethyl [0324] Et.sub.2O diethyl ether [0325]
Et.sub.3N triethylamine [0326] EtOAc ethyl acetate [0327] EtOH
ethanol [0328] Ex example [0329] g gram [0330] GC-MS gas
chromatography-mass spectrometry [0331] h hour(s) [0332] HATU
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0333] HBTU
O-(Benzotriazol-1-yl)-N,N,N,N'-tetramethyluronium
hexafluorophosphate [0334] Hex hexanes [0335] [3H] MLA tritiated
methyllycaconitine citrate [0336] .sup.1H NMR proton nuclear
magnetic resonance [0337] HOAT 1-hydroxy-7-aza-benzotriazole [0338]
HOBT 1-hydroxybenzotriazole [0339] HPLC high-performance liquid
chromatography [0340] HPLC ES-MS high-performance liquid
chromatography-electrospray mass spectroscopy [0341] Int
intermediate [0342] KOtBu potassium tert-butoxide [0343] L liter
[0344] LCMS liquid chromatography/mass spectroscopy [0345] m
multiplet [0346] M molar [0347] mL milliliter [0348] m/z mass over
charge [0349] Me methyl [0350] MeCN acetonitrile [0351] MeOH
methanol [0352] mg milligram [0353] MHz megahertz [0354] min
minute(s) [0355] mmol millimole [0356] mol mole [0357] mp melting
point [0358] MS mass spectrometry [0359] N normal [0360] NaOAc
sodium acetate [0361] NBS N-bromosuccinimide [0362] NMM
4-methylmorpholine [0363] .sup.1H NMR nuclear magnetic resonance
[0364] Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone)dipalladium(0)
[0365] Pd(OAc).sub.2 palladium acetate [0366] Pd(PPh.sub.3).sub.4
tetrakis(triphenylphosphine)palladium(0) [0367] Pd/C palladium on
carbon [0368] Pd(dppf)Cl.sub.2
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [0369]
Ph phenyl [0370] ppm parts per million [0371] Pr propyl [0372] psi
pounds per square inch [0373] q quartet [0374] qt quintet [0375]
R.sub.f TLC retention factor [0376] rt room temperature [0377] s
singlet [0378] t triplet [0379] t.sub.R retention time (HPLC)
[0380] TBAF tetrabutylammonium fluoride [0381] TBSCl
tert-butyldimethylsilyl chloride [0382] TBS tert-butyldimethylsilyl
[0383] TBTU O-(Benzotriazol-1-yl)-N,N,N,N'-tetramethyluronium
tetrafluoroborate [0384] TFA trifluoroacetic acid [0385] THF
tetrahydrofuran [0386] TLC thin layer chromatography [0387] TMS
tetramethylsilane [0388] pTSA 4-methylbenzenesulfonic acid
(p-toluenesulfonic acid) [0389] v/v volume per unit volume [0390]
vol volume [0391] w/w weight per unit weight
[0392] The following specific examples are presented to further
illustrate the invention described herein, but they should not be
construed as limiting the scope of the invention in any way.
Experimental Examples
General
[0393] .sup.1HNMR spectra are recorded at 300 MHz on a Bruker
Instruments NMR unless otherwise stated. Coupling constants (J) are
in Hertz (Hz) and peaks are listed relative to TMS (.delta. 0.00
ppm).
[0394] Sulfonic acid ion exchange resins (SCX) are purchased from
Varian Technologies.
[0395] Analytical HPLC//MS is performed on Waters Micromass using
4.6 mm.times.100 mm Xterra RP.sub.18 3.5.mu. columns using (i) a
gradient of 20/80 to 80/20 acetonitrile (0.1% formic acid)/water
(0.1% formic acid) over 8 min (Method A), or (ii) a gradient of
5/95 to 80/20 acetonitrile (0.1% formic acid)/water (0.1% formic
acid) over 8 min (Method B). Preparative HPLC is performed on 20
mm.times.250 mm 5.mu. SHISEIDO, CAPCELL PAK C18 column using a
gradient of 90/10 to 0/100 water/acetonitrile over 25 minutes while
monitoring .lamda.254 nm in the UV spectrum.
[0396] Many of the carboxylic acids used in the experimental are
commercially available. The procedure to prepare the carboxylic
acids that are not commercially available is provided below.
1,4-Diazabicyclo[3.2.2]nonane dihydrochloride was purchased from
Olainfarm. Hydrochloride salts of the bicycle amides are prepared
by adding an ethereal solution of hydrochloric acid to a methanolic
solution of the bicyclic amide, followed by isolation of the
resulting precipitate.
[0397] Other carboxylic acids used in the experimental are prepared
by straightforward synthetic methods known to those skilled in the
art, for example, using the method illustrated in Procedures 1-5
described below:
Procedure 1.
[0398] The following procedure describes the preparation of
substituted and modified dihydrochromen-4-ones from phenols:
##STR00058##
Dihydrochromen-4-one Synthesis (Ketone Synthesis 1)
[0399] A solution of 2-methoxyphenol (40.3 mmol) in potassium
hydroxide (15 mL) is added to a solution of 3-chloropropanoic acid
(40.7 mmol) and sodium bicarbonate (40.5 mmol) in water (15 mL).
The reaction mixture is heated at 110.degree. C. for 16 h and is
allowed to cool to rt. The pH of the reaction mixture is
adjusted.to 5 with 10% aqueous hydrochloric acid and is extracted
with ether (3.times.100 mL). The combined organic layers are
extracted with sodium bicarbonate (3.times.80 mL) and the pH of the
combined aqueous layers is adjusted to 5 with 10% aqueous
hydrochloric acid. The aqueous layer is extracted with
dichloromethane (150 mL), dried (sodium sulfate), and concentrated
to provide 3-(2-methoxyphenoxy)propanoic acid (Target B) in 14%
yield as a yellow solid.
[0400] 3-(2-Methoxyphenoxy)propanoic acid (5.61 mmol) and
polyphosphoric (25 mL) are combined and heated at 67.degree. C. for
1 h. The reaction mixture is diluted with ice water (150 mL) and
the precipitated solids are collected by filtration, washed with
water, and dried to provide 8-methoxy-2,3-dihydrochromen-4-one
(Target C2) in 67% yield as a brown solid.
[0401] The following dihydrochromen-4-ones are prepared using this
procedure, starting from the appropriately substituted phenols:
[0402] 8-Methoxy-2,3-dihydrochromen-4-one. [0403]
7-Methoxy-2,3-dihydrochromen-4-one. [0404]
6-Methoxy-2,3-dihydrochromen-4-one. [0405]
7-Bromo-2,3-dihydrochromen-4-one. [0406]
3,4-Dihydronaphthalen-1(2H)-one is commercially available.
Procedure 2.
[0407] The following procedure describes the preparation of
tetrahydroquinolin-5-one from cyclohexane-1,3-dione:
##STR00059##
Tetrahydroquinolin-5-one Synthesis (Ketone Synthesis 2)
[0408] Ammonium acetate (151 mmol) and cyclohexane-1,3-dione
(150.00 rnmol) are combined and diluted with toluene (300 mL) in a
round bottom flask with a Dean-Stark condenser. The reaction
mixture is heated at reflux for 4 h and is concentrated. The solid
residue is recrystallized (ethyl acetate) to provide
3-amino-2-cyclohexen-1-one as a yellow solid. The material is of
sufficient purity to use in the subsequent transformation.
[0409] A mixture of 3-aminocyclohex-2-enone (100 mmol),
1,1,3,3-tetraethoxypropane (110 mmol), and 4-methylbenzenesulfonic
acid (2.91 mmol) is diluted with N,N-dimethylformamide (40 mL) and
the reaction mixture is heated at reflux for 16 h. The reaction
mixture is allowed to cool to rt, neutralized with sodium
bicarbonate, diluted with water (400 mL), and is extracted with
ethyl acetate (3.times.100 mL). The combined organic layers are
dried (sodium sulfate) and concentrated. The residue is purified by
chromatography (10/1 petroleum ether/ethyl acetate) to provide
5,6,7,8-tetrahydroquinolin-5-one in 7% yield as a colorless
oil.
[0410] The following tetrahydroquinolin-5-one is prepared using
this method: 5,6,7,8-Tetrahydroquinolin-5-one.
Procedure 3.
[0411] The following procedure describes the synthesis of
isochromen-4(3H)-ones from 2-methylbenzonitriles:
##STR00060##
1H-Isochromen-4(3H)-one Synthesis (Ketone Synthesis 3)
[0412] Azobisisobutyronitrile (AIBN, 29.25 mmol) is added to a
solution of 2-methylbenzonitrile (325 mmol) and N-bromosuccinimide
(NBS, 346 mmol) in carbontetrachloride (300 mL). The reaction
mixture is heated at 90.degree. C. for 2 h and is allowed to cool
to rt. The precipitated solids are removed by filtration and the
filtrate is washed with saturated aqueous sodium bicarbonate
(4.times.120 mL), dried (sodium sulfate), and concentrated. The
resulting solid is washed with hexane (4.times.500 mL) and dried to
provide 2-(bromomethyl)benzonitrile in 57% yield as a yellow solid.
A solution of 2-(bromomethyl)benzonitrile (214 mmol) in
dimethylsulfoxide (40 mL) is added over 90 min to a solution of
ethyl 2-hydroxyacetate (431 mmol) and sodium ethoxide (215 mmol) in
dimethylsulfoxide (14.5 mL). The reaction mixture is maintained at
it for 1 h, is heated at 65.degree. C. for 5 h, and is allowed to
cool to rt. The reaction mixture is diluted with ice water (50 g)
and extracted with ether (3.times.500 mL) and the combined organic
layers are dried (sodium sulfate), and concentrated. The residue is
purified by chromatography (100/1 to 50/1 petroleum ether/ethyl
acetate) to provide ethyl [(2-cyanobenzyl)oxy]acetate as a yellow
oil.
[0413] Potassium hydroxide (309 mmol) is added to a solution of
ethyl [(2-cyanobenzyl)oxy]acetate (62.5 mmol) in ethanol (60 mL)
and water (60 mL). The reaction mixture is heated at 90.degree. C.
for 16 h, allowed to cool to rt, and the pH adjusted to .about.1
with concentrated hydrochloric acid. The resulting solution is
extracted with dichloromethane (3.times.100 mL) and the combined
organic layers are dried (sodium sulfate), and concentrated to
provide crude 2-[(carboxymethoxy)methyl]benzoic acid as a brown
solid. The material is of sufficient purity to use in the
subsequent step. 2-[(Carboxymethoxy)methyl]benzoic acid (37.6 mmol)
and potassium acetate (169.2 mmol) are combined and diluted with
acetic anhydride (112 mL). The reaction mixture is heated at
138.degree. C. for 2 h and is concentrated. The residue is diluted
with ice water (25 g), extracted with ether (3.times.900 mL) and
the combined organic layers are dried (magnesium sulfate), and
concentrated. The residue is diluted with ethanol (150 mL) and 4 N
sodium hydroxide (20 mL) and the reaction mixture is maintained for
2 h at rt. The reaction mixture is extracted with ether
(3.times.900 mL) and the combined organic layers are dried
(magnesium sulfate), and concentrated. The residue is purified by
chromatography (100/1 to 30/1 hexane/ethyl acetate) to provide
1H-isochromen-4(3H)-one in 47% yield as a yellow oil.
[0414] The following isochromenone is prepared using this
procedure:
[0415] 1H-Isochromen-4(3H)-one
Procedure 4.
[0416] The following procedure describes the preparation of
pyrazole carboxylic acids, starting from ketones, either
commercially available or prepared as described above by Procedures
1-3:
##STR00061##
Dihydrochromeno[4,3-c]pyrazole acid Synthesis
[0417] Sodium hexamethyldisilazide (1 M in tetrahydrofuran, 4.02
mmol) is added dropwise to a solution of
8-methoxy-2,3-dihydrochromen-4-one (C2, 3.93 mmol) in
tetrahydrofuran (20 mL) at -78.degree. C. and the reaction mixture
is maintained for 30 min Diethyl oxalate (4.02 mmol) is added
dropwise and the reaction mixture is allowed to warm to it and
maintained for 1 h. The reaction mixture is diluted with 10%
aqueous hydrochloric acid (20 mL) and is extracted with ethyl
acetate (150 mL). The organic layer is dried (magnesium sulfate)
and concentrated to provide ethyl
2-(8-methoxy-4-oxo-3,4-dihydro-2H-chromen-3-yl)-2-oxoacetate
(Target L) in 96% yield as yellow oil.
[0418] Hydrazine hydrate (4.00 mmol) is added to a solution of
ethyl 2-(8-methoxy-4-oxo-3,4-dihydro-2H-chromen-3-yl)-2-oxoacetate
(L, 3.96 mmol) in ethanol (40 mL) and the reaction mixture is
heated at reflux for 1 h. The reaction mixture is diluted with ice
water (140 mL), extracted with ethyl acetate (200 mL), dried
(sodium sulfate), and concentrated to provide ethyl
6-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (Target
M) in 65% yield as a yellow solid.
[0419] A solution of sodium hydroxide (12.8 mmol) in water (10 mL)
is added to a solution of ethyl
6-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (M, 2.43
mmol) in ethanol (100 mL). The reaction mixture is heated at reflux
for 3 h and is concentrated. The residue is diluted with water (100
mL) and is extracted with ethyl acetate (200 mL). The pH of the
aqueous layer is adjusted to 2-3 with 10% aqueous hydrochloric acid
and the precipitated solids are collected by filtration, washed
with water and hexane, and dried to provide
6-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid
(Target N) in 64% yield as a yellow solid. .sup.1H-NMR
(DMSO-d.sub.6): .delta. 7.2 (1H, d), 6.9 (2H, m), 5.4 (2H, s), 3.7
(3H, s); LC/MS (ES, m/z) [M+1]+247.
[0420] The following substituted dihydrochromeno[4,3-c]pyrazole
acids are prepared using this method, starting from the appropriate
ketone: [0421]
6-Methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid.
[0422] 7-Methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic
acid [0423] 7-Bromo-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic
acid. [0424]
8-Methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid.
[0425] 4,5-Dihydro-1H-benzo[g]indazole-3-carboxylic acid. [0426]
4,5-Dihydro-1H-pyrazolo[3,4-f]quinoline-3-carboxylic acid. [0427]
1,5-Dihydroisochromeno[4,3-c]pyrazole-3-carboxylic acid.
Procedure 5.
[0428] The following procedure describes a method to prepare
6-(4-fluorophenyl)-4,5-dihydro-1H-indazole-3-carboxylic acid
##STR00062##
A solution of 3-ethoxy-2-cyclohexen-1-one (15.0 mmol) in
tetrahydrofuran (7.5 mL) is added over 10 min to a solution of
4-fluorophenylmagnesium bromide (1.0 M in tetrahydrofuran, 15.0 mL)
in tetrahydrofuran (7.5 mL) at -5.degree. C. The reaction mixture
is maintained for 30 min, is allowed to warm to rt and is
maintained for an additional 2 h. The solution is poured into 1 N
aqueous hydrochloric acid and is maintained for 1 h. The reaction
mixture is diluted with water (50 mL) and extracted with ethyl
acetate (50 mL). The organic layer is washed with brine (25 mL),
dried (magnesium sulfate), and concentrated. The residue is
purified by chromatography (90/10 to 65/35 hexanes/ethyl acetate)
to provide 3-(4-fluorophenyl)cyclohex-2-en-1-one in 49% yield.
[0429] A solution of 3-(4-fluorophenyl)cyclohex-2-en-1-one (7.40
mmol) in ether (10.0 mL) is added to a solution of lithium
hexamethyldisilazide (1.00 M in tetrahydrofuran, 8.0 mL) in ether
(10.0 mL) at -78.degree. C. After 15 min, a solution of ethanedioic
acid, dimethyl ester (11.0 mmol) in ether (10.0 mL) is added and
the reaction mixture is allowed to warm to it and is maintained for
16 h. The reaction mixture is partitioned between water (50 mL) and
ethyl acetate (50 mL) and is neutralized with 1N hydrochloric acid.
The layers are separated and the organic layer is washed with brine
(25 mL), dried (magnesium sulfate), and concentrated to provide a
yellow solid. The solid is recrystallized (ethanol) to provide
methyl [4-(4-fluorophenyl)-2-oxocyclohex-3-en-1-yl](oxo)acetate
in73% yield as a light yellow solid.
[0430] Hydrazine (3.80 mmol) is added to a solution of methyl
[4-(4-fluorophenyl)-2-oxocyclohex-3-en-1-yl](oxo)acetate (2.70
mmol) in ethanol (10.0 mL) and t reaction mixture is heated at
reflux for 30 min. The mixture is allowed to cool to it and the
precipitated solids are collected by filtration to give methyl
6-(4-fluorophenyl)-4,5-dihydro-1H-indazole-3-carboxylate in 80%
yield as an off-white solid. The acid is prepared by standard
saponification conditions (sodium hydroxide in ethanol/water) and
used without further purification.
[0431] The following acid is prepared using this method: [0432]
6-(4-Fluorophenyl)-4,5-dihydro-1H-indazole-3-carboxylic acid.
Procedure 6.
[0433] The following procedure describes the synthesis of
isothiazole-3-carboxylic acid from 5-amino-3-methylisothiazole
hydrochloride.
##STR00063##
Sodium nitrite (36.4 mmol) is added in several batches to a
solution of 5-amino-3-methylisothiazole hydrochloride (33.1 mmol)
in sulfuric acid (25 mL) at 0.degree. C. A solution of copper(II)
oxide (1.67 mmol) in 30% phosphoric acid (70 mL) is added dropwise
to the solution and the reaction mixture is maintained at 0.degree.
C. for 1 h. The reaction mixture is warmed to 40.degree. C. and is
maintained for an additional 1 h. The pH of the reaction mixture is
adjusted to .about.9 with 25% sodium hydroxide and is extracted
with ether (3.times.100 mL). The combined organic layers are dried
(sodium sulfate) and concentrated to provide 3-methylisothiazole in
12% yield as yellow oil.
[0434] Chromium(IV) oxide (9.00 mmol) is added in several batches
to a solution of 3-methylisothiazole (3.03 mmol) in fuming sulfuric
acid (10 mL) at 0.degree. C. The reaction mixture is allowed to
warm to rt and is maintained for 16 h. The reaction mixture is
diluted with ice water (100 mL), extracted with ether (6.times.200
mL) and the combined organic layers are dried (sodium sulfate) and
concentrated. The residue is purified by preparative HPLC to
provide isothiazole-3-carboxylic acid in 13% yield as a white
solid. .sup.1H-NMR (400MHz, DMSO-d.sub.6) .delta. 3.43 (s, 1H),
9.17 (d, 1H), 7.80 (d, 1H), 3.43 (s, 1H); LC/MS (ES, m/z)
[M+1].sup.+ 128.
[0435] The following acid is prepared using this method: [0436]
Isothiazole-3-carboxylic acid.
Procedure 7.
[0437] The following procedure describes the preparation of
5-bromoisothiazole-3-carboxylic acid from
5-amino-3-methylisothiazole hydrochloride.
##STR00064##
A solution of sodium nitrite (66.7 mmol) in water (6 mL) is added
dropwise to a solution of 3-methylisothiazol-5-amine hydrochloride
(66.2 mmol) in phosphoric acid (25 mL) and nitric acid (13 mL) at
0.degree. C. and the reaction mixture is maintained for 30 min. A
solution of copper(I) bromide (66.2 mmol) in concentrated
hydrobromic acid (50 mL) is added dropwise and the reaction mixture
is maintained at 0.degree. C. for 60 min when the pH of the
solution is adjusted to .about.4 with 2 N sodium hydroxide (100
mL). The resulting solution is extracted with ether (3.times.200
mL) and the combined organic layers are dried (sodium sulfate) and
concentrated. The solid residue is recrystallized from petroleum
ether/ethyl acetate to provide 5-bromo-3-methylisothiazole in 13%
yield as a yellow oil.
[0438] Chromium(IV) oxide (21.9 mmol) is added in several batches
to a solution of 5-bromo-3-methylisothiazole (7.30 mmol) in fuming
sulfuric acid (30 mL) at 0.degree. C. The reaction mixture is
allowed to warm to it and is maintained for 16 h. The reaction
mixture is diluted with ice water (100 mL), extracted with ether
(3.times.200 mL) and the combined organic layers are dried (sodium
sulfate) and concentrated. The residue is purified by preparative
HPLC to provide 5-bromoisothiazole-3-carboxylic acid in 13% yield
as a white solid. .sup.1H-NMR (DMSO-d.sub.6): .delta. 13.8 (broad
s, 1H), 7.9 (s, 1H); LC/MS (ES, m/z) [M].sup.+ 208
[0439] The following acid is prepared using this procedure: [0440]
5-Bromoisothiazole-3-carboxylic acid.
[0441] Hydrochloride salts of the bicycle amides are prepared by
adding an ethereal solution of hydrochloric acid to a methanolic
solution of the bicyclic amide, followed by isolation of the
resulting precipitate.
Procedure 8.
[0442] The following procedure describes the synthesis of
7-[(3S)-3-methoxypyrrolidin-1-yl]-1,4-dihydrochromeno[4,3-c]pyrazole-3-ca-
rboxylic acid hydrochloride from ethyl
7-bromo-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate.
##STR00065##
3,4-Dihydro-2H-pyran (11.9 mmol) and 4-methylbenzenesulfonic acid
(0.58 mmol) are added to a solution of ethyl
7-bromo-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (9.29
mmol) in dichloromethane (100 mL) and tetrahydrofuran (20 mL) and
the reaction mixture is maintained at it for 16 h. The reaction
mixture is washed with water (3.times.100 mL), dried (sodium
sulfate), and concentrated to provide ethyl
7-bromo-1-(tetrahydro-2H-pyran-2-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-
-carboxylate in 43% yield as a brown solid.
[0443] A mixture of ethyl
7-bromo-1-(tetrahydro-2H-pyran-2-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-
-carboxylate (3.98 mmol), (S)-3-methoxypyrrolidine (8.02 mmol),
BINAP (0.48 mmol), cesium carbonate (10.1 mmol),and palladium(II)
acetate (0.40 mmol) under an atmosphere of nitrogen is diluted with
toluene (100 mL). The reaction mixture is heated at 110.degree. C.
for 16 h and is concentrated. The residue is diluted with water (50
mL) and is extracted with ethyl acetate (3.times.300 mL) and the
combined organic layers are dried (sodium sulfate) and
concentrated. The residue is purified by chromatography (20/1 to
10/1 petroleum ether/ethyl acetate) to provide ethyl
7-[(3S)-3-methoxypyrrolidin-1-yl]-1-(tetrahydro-2H-pyran-2-yl)-1,4--
dihydrochromeno[4,3-c]pyrazole-3-carboxylate in 59% yield as a
white solid.
[0444] A solution of sodium hydroxide (10.0 mmol) in water (5 mL)
is added to a solution of ethyl
7-[(3S)-3-methoxypyrrolidin-1-yl]-1-(tetrahydro-2H-pyran-2-yl)-1,4-dihydr-
ochromeno[4,3-c]pyrazole-3-carboxylate (1.87 mmol) in ethanol (35
mL) and the reaction m mixture is heated at 90.degree. C. for 1 h.
The reaction mixture is concentrated, diluted with water (35 mL),
and extracted with ethyl acetate (3.times.300 mL). The pH of the
combined aqueous layers is adjusted to .about.3 with 10% aqueous
hydrochloric acid and is concentrated to provide
7-[(3S)-3-methoxypyrrolidin-1-yl]-1-(tetrahydro-2H-pyran-2-yl)-1,4-dihydr-
ochromeno[4,3-c]pyrazole-3-carboxylic acid in 45% yield as a white
solid. Gaseous hydrochloric acid is bubbled through a solution of
7-[(3S)-3-methoxypyrrolidin-1-yl]-1-(tetrahydro-2H-pyran-2-yl)-1,4-dihydr-
ochromeno[4,3-c]pyrazole-3-carboxylic acid (0.85 mmol) in
1,4-dioxane (60 mL) for 30 min. The reaction mixture is maintained
for 2 h at rt and is concentrated. The crude product is purified by
preparative HPLC to provide
7-[(3S)-3-methoxypyrrolidin-1-yl]-1,4-dihydrochromeno[4,3-c]pyraz-
ole-3-carboxylic acid hydrochloride in 19% yield as a yellow
solid.
[0445] The following acid is prepared using this method: [0446]
7-[(3S)-3-methoxypyrrolidin-1-yl]-1,4-dihydrochromeno[4,3-c]pyrazole-3-ca-
rboxylic acid hydrochloride.
Representative Preparative Examples of the Invention Compounds
Example 1
Preparation of
4-[(4-Chloro-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
(Representative Procedure A)
##STR00066##
[0448] The following provides a general method for the coupling of
bicyclobases and carboxylic acids to form carboxamide
derivatives.
[0449] A solid mixture of 4-chloro-1H-pyrazole-3-carboxylic acid
(1.47 mmol),
N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (HATU) (1.06 mmol), and
1,4-diazabicyclo[3.2.2]nonane dihydrochloride (0.979 mmol) is
diluted with N,N-dimethylformamide (6.0 mL) and
N,N-diisopropylethylamine (5.7 mmol) and the reaction mixture is
maintained for 16 h at rt. The reaction mixture is transferred to a
SCX column (10 g) and flushed with 5 volumes of methanol. The
partially purified product is then eluted using 2.0 M ammonia in
methanol and concentrated. The residue is purified by gradient
preparative chromatography, starting from 100/0 to 50/50 ratio
mixture of solvent A/solvent B, where A=ethyl acetate and B is
(50/50/2) ethyl acetate/methanol/dimethylethylamine, to provide the
product in 64% yield as an off-white solid.
[0450] .sup.1H NMR (CD.sub.3OD) .delta. [3/1 rotamer mixture] 7.80
(s, 1H), 4.71 (m, 0.75H), 4.10 (m, 0.25H), 3.98 (m, 0.5H), 3.68 (m,
1.5H), 3.09-2.98 (m, 6H), 2.17-1.84 (four m, 4H). LC/MS (EI)
t.sub.R 1.45 min (Method A), m/z 255.1.min.
[0451] Using Procedure A described above for Example 1, the
following carboxamide derivative compounds of Examples 2-38 can be
similarly prepared and are characterized below:
Example 2
4-[(4-Nitro-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
##STR00067##
[0453] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
4-nitro-1H-pyrazole-3-carboxylic acid: LC/MS (EI) t.sub.R 3.90 min
(Method B), m/z 266.1.
Example 3
4-[(5-Methyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
##STR00068##
[0455] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-methyl-1H-pyrazole-3-carboxylic acid: LC/MS (EI) t.sub.R 1.42 min
(Method A), m/z 235.1.
Example 4
4-(1H-Pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane
##STR00069##
[0457] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
1H-pyrazole-3-carboxylic acid: LC/MS (EI) t.sub.R 4.40 min (Method
B), m/z 221.1.
Example 5
4-([5-(4-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]n-
onane
##STR00070##
[0459] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-(4-methoxyphenyl)-1H-pyrazole-3-carboxylic acid: LC/MS (EI)
t.sub.R 2.58 min (Method A), m/z 327.1.
Example 6
4-[(5-Phenylisoxazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
##STR00071##
[0461] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-phenylisoxazole-3-carboxylic acid: LC/MS (EI) t.sub.R 3.53 min
(Method A), m/z 298.1.
Example 7
4-{[5-(2-Thienyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonane
##STR00072##
[0463] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-(2-thienyl)-1H-pyrazole-3-carboxylic acid: LC/MS (EI) t.sub.R
2.54 min (Method A), m/z 303.
Example 8
4-[(5-phenyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
##STR00073##
[0465] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-phenyl-1H-pyrazole-3-carboxylic acid: LC/MS (EI) t.sub.R 2.58 min
(Method A), m/z 297.1.
Example 9
4-[(5-Cyclopropyl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
##STR00074##
[0467] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-cyclopropyl-1H-pyrazole-3-carboxylic acid: LC/MS (EI) t.sub.R
1.55 min (Method A), m/z 261.2.
Example 10
4-{[5-(3-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]n-
onane
##STR00075##
[0469] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-(3-methoxyphenyl)-1H-pyrazole-3-carboxylic acid: LC/MS (EI)
t.sub.R 2.64 min (Method A), m/z 327.2.
Example 11
4-(1,4,5,6-Tetrahydrocyclopenta[c]pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[3-
.2.2]nonane
##STR00076##
[0471] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
1,4,5,6-tetrahydrocyclopentapyrazole-3-carboxylic acid: LC/MS (EI)
t.sub.R 1.52 min (Method A), m/z 261.2.
Example 12
4-{[5-(2-Methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]n-
onane
##STR00077##
[0473] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-(2-methoxyphenyl)-1H-pyrazole-3-carboxylic acid:
[0474] LC/MS (EI) t.sub.R 2.63 min (Method A), m/z 327.2.
Example 13
4-[(4-Bromo-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
##STR00078##
[0476] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
4-bromo-1H-pyrazole-3-carboxylic acid: LC/MS (EI) t.sub.R 1.47 min
(Method A), m/z 299/301.
Example 14
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)isothiazol-4-amine
##STR00079##
[0478] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
4-aminoisothiazole-3-carboxylic acid: LC/MS (EI) t.sub.R 1.41 min
(Method A), m/z 253.1.
Example 15
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4,3-c]pyra-
zole
##STR00080##
[0480] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid: LC/MS (EI)
t.sub.R 2.77 min (Method A), m/z 325.1.
Example 16
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5,6,7,8,9-hexahydro-1H-cyclo-
octa[c]pyrazole
##STR00081##
[0482] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid: LC/MS
(EI) t.sub.R 2.54 min (Method A), m/z 303.1.
Example 17
4-{[5-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-yl]carbonyl}-1,4-dia-
zabicyclo[3.2.2]nonane
##STR00082##
[0484] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1H-pyrazole-3-carboxylic acid:
LC/MS (EI) t.sub.R 2.54 min (Method A), m/z 355.1
Example 18
4-{[5-(2-Naphthyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonane
##STR00083##
[0486] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-naphthalen-2-yl-1H-pyrazole-3-carboxylic acid: LC/MS (EI) t.sub.R
3.79 min (Method A), m/z 347.2.
Example 19
4-{[5-(3-Thienyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]nonane
##STR00084##
[0488] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-thiophen-3-yl-1H-pyrazole-3-carboxylic acid: LC/MS (EI) t.sub.R
2.54 min (Method A), m/z 303.1.
Example 20
4-{[5-(4-Fluorophenyl)-1H-pyrazol-3-yl]carbonyl}-1,4-diazabicyclo[3.2.2]no-
nane
##STR00085##
[0490] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-(4-fluorophenyl)-1H-pyrazole-3-carboxylic acid: LC/MS (EI)
t.sub.R 2.63 min (Method A), m/z 315.1.
Example 21
4-[(5-Pyridin-2-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
##STR00086##
[0492] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-pyridin-2-yl-1H-pyrazole-3-carboxylic acid: LC/MS (EI) t.sub.R
1.42 min (Method A), m/z 298.2.
Example 22
4-[(5-Pyridin-4-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
##STR00087##
[0494] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-pyridin-4-yl-1H-pyrazole-3-carboxylic acid: LC/MS (EI) t.sub.R
1.35 min (Method A), m/z 298.1
Example 23
4-[(5-Pyridin-3-yl-1H-pyrazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
##STR00088##
[0496] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
5-pyridin-3-yl-1H-pyrazole-3-carboxylic acid: LC/MS (EI) t.sub.R
1.40 min (Method A), m/z 298.1.
Example 24
5'-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1-methyl-1H,2'-3,3'-bipyrazol-
e
##STR00089##
[0498] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
1'-methyl-2H,1'H-[3,3]bipyrazolyl-5-carboxylic acid: LC/MS (EI)
t.sub.R 1.45 min (Method A), m/z 301.2.
Example 25
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,4-dihydrochromeno[-
4,3-c]pyrazole
##STR00090##
[0500] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
6-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid:
LC/MS (EI) t.sub.R 2.55 min (Method A), m/z 355.2.
Example 26
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-8-methoxy-1,4-dihydrochromeno[-
4,3-c]pyrazole
##STR00091##
[0502] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
8-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid:
LC/MS (EI) t.sub.R 2.94 min (Method A), m/z 355.2.
Example 27
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-methoxy-1,4-dihydrochromeno[-
4,3-c]pyrazole
##STR00092##
[0504] The compound is prepared as described for Example 1 starting
from 1,4-diazabicyclo[3.2.2]nonane dihydrochloride and
8-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid:
LC/MS (EI) t.sub.R 2.87 min (Method A), m/z 355.2.
Example 28
(1H-Pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane
Hydrochloride
(Representative Procedure B)
##STR00093##
[0506] The following provides a general method for the production
of salts of the bicyclobase adducts created using Representative
Procedure A.
[0507] 4-(1H-Pyrazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane is
prepared from 1H-pyrazole-3-carboxylic acid and
1,4-diazabicyclo[3.2.2]nonane dihydrochloride using Example 1 in
71% yield. The amide (0.645 mmol) is dissolved in methanol (5 mL)
and treated with 1 M hydrochloric acid in ether (7 mL). The
reaction mixture is maintained for 2 h and is diluted with ether
(15 mL) to induce more crystallization. The solids are isolated and
recrystallized from methanol/ethyl acetate to provide the salt in
46% yield as a colorless solid.
[0508] .sup.1HNMR: CD.sub.3OD .delta. 7.76 (s, 1H), 6.73 (s, 1H),
5.20 (broad s, 1H), 4.47 (m, 1H), 4.18 (m, 1H), 3.64-3.52 (m, 7H),
2.35 (m, 2H), 2.18 (M, 2H).
[0509] Using Procedure B described above for Example 28, the
following compound of Examples 29 can be similarly prepared and is
characterized below:
Example 29
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4,3-c]pyra-
zole hydrochloride
##STR00094##
[0511] The compound is prepared as described for Example 28
starting from the compound prepared in Example 15: LC/MS (EI)
t.sub.R 2.82 min (Method A), m/z 325.1.
Example 30
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(4-fluorophenyl)-4,5-dihydro-
-1H-indazole
##STR00095##
[0513] The compound is prepared as described for Example 1 starting
from 6-(4-fluorophenyl)-4,5-dihydro-1H-indazole-3-carboxylic acid:
LC/MS (EI) t.sub.R 3.83 (Method A), m/z 367.2.
Example 31
4-(Isothiazol-3-ylcarbonyl)-1,4-diazabicyclo[3.2.2]nonane
##STR00096##
[0515] The compound is prepared as described for Example 1 starting
from isothiazole-3-carboxylic acid: LC/MS (EI) t.sub.R 1.47 min
(Method A), m/z 238.1.
Example 32
4-[(5-Bromoisothiazol-3-yl)carbonyl]-1,4-diazabicyclo[3.2.2]nonane
##STR00097##
[0517] The compound is prepared as described for Example 1 starting
from 5-bromoisothiazole-3-carboxylic acid: LC/MS (EI) t.sub.R 2.55
(Method A), m/z 316.01318.0.
Example 33
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5-dihydro-1H-benzo[g]indazol-
e
##STR00098##
[0519] The compound is prepared as described for Example 1 starting
from 4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid: LC/MS (EI)
t.sub.R 2.53 min (Method A), m/z 323.2.
Example 34
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,5-dihydroisochromeno[4,3-c]p-
yrazole
##STR00099##
[0521] The compound is prepared as described for Example 1 starting
from 1,5-dihydroisochromeno[4,3-c]pyrazole-3-carboxylic acid LC/MS
(EI) t.sub.R 2.42 min (Method A), m/z 325.
Example 35
3-(1,4-Dazabicyclo[3.2.2]non-4-ylcarbonyl)-4,5-dihydro-1H-pyrazolo[3,4-f]q-
uinoline
##STR00100##
[0523] The compound is prepared as described for Example 1 starting
from 4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-3-carboxylic acid:
LC/MS (EI) t.sub.R 1.27 min (Method A), m/z 324.1.
Example 36
3-(1,4-Dazabicyclo[3.2.2]non-4-ylcarbonyl)-74(3S)-3-methoxypyrrolidin-1-yl-
]-1,4-dihydrochromeno[4,3-c]pyrazole
##STR00101##
[0525] The compound is prepared as described for Example 1 starting
from
7-[(3S)-3-methoxypyrrolidin-1-yl]-1,4-dihydrochromeno[4,3-c]pyrazole-3-ca-
rboxylic acid: LC/MS (EI) t.sub.R 3.38 min (Method A), m/z
424.2.
Example 37
7-Bomo-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,4-dihydrochromeno[4,3-
-c]pyrazole
##STR00102##
[0527] The compound is prepared as described for Example 1 starting
from 7-bromo-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid
LC/MS (EI) t.sub.R 3.87 min (Method A), m/z 402.1/405.0.
Example 38
3-(1,4-Dzabicyclo[3.2.2]non-4-ylcarbonyl)-1H-pyrazol-5-amine
##STR00103##
[0529] The compound is prepared as described for Example 1 starting
from 5-aminopyrazole-3-carboxylic acid LC/MS (EI) t.sub.R 1.42 min
(Method A), m/z 236.1.
Example 39
Evaluation of Compounds with a [3H] MLA Binding Assay
[0530] The procedure for [.sup.3H]MLA binding assay is the same as
described in WO2004/029050 A1, except the receptor resource is
humanized monkey .alpha.7 receptors (See WO 03/095976).
Materials:
[0531] Humanized monkey .alpha.7 receptors
[0532] Protease inhibitor cocktail tablet: Roche, CAT No.
1697498
Membrane Preparation
[0533] Rat brains in 20 vol (wlv) of ice-cold 0.32 M sucrose with
protease inhibitors (one tablet per 50 ml,) are homogenized with a
polytron for 10 sec at setting 11, then centrifuged 10 min at 1000
g, 4.degree. C. The supernatant is centrifuged again for 20 min at
20,000 g, 4.degree. C. The pellets are resuspended in binding
buffer (200 mM TRIS-HCl, 20 mM HEPES, pH 7.5, 144 mM NaCl, 1.5 mM
KCl, 1 mM MgSO.sub.4, 2 mM CaCl.sub.2, 0.1% (wlv) BSA) and stored
membrane prep at -80.degree. C.
[0534] For saturation assay, the 200 .mu.l assay mixture in binding
buffer contains 200 .mu.g of membrane protein, 0.2 to 44 nM of [3H]
MLA. The nonspecific binding is defined using 1 .mu.M MLA.
Competition assay is carried out with 2 nM [3H] MLA and a desirable
range of compounds. The assay mixture is incubated at 22.degree. C.
for 2 hours. Binding affinities for the preferred compounds of the
invention are 3 nM to 10 .mu.M.
Capsule Formulation
[0535] A capsule formula is prepared from:
TABLE-US-00002 Formula (I) compound 10 mg Starch 109 mg Magnesium
stearate 1 mg
The components are blended, passed through an appropriate mesh
sieve, and filled into hard gelatin capsules.
Tablet Formulation
[0536] A tablet is prepared from:
TABLE-US-00003 Formula (I) compound 25 mg Cellulose,
microcrystaline 200 mg Colloidal silicon dioxide 10 mg Stearic acid
5.0 mg
The ingredients are mixed and compressed to form tablets.
Appropriate aqueous and non-aqueous coatings may be applied to
increase palatability, improve elegance and stability or delay
absorption.
Sterile IV Solution
[0537] A mg/mL solution of the Formula (I) compound is made using
sterile, injectable water, and the pH is adjusted if necessary. The
solution is diluted for administration with sterile 5% dextrose and
is administered as an IV infusion.
Intramuscular Suspension
[0538] The following intramuscular suspension is prepared:
TABLE-US-00004 Formula (I) compound 50 .mu.g/mL Sodium
carboxymethylcellulose 5 mg/mL TWEEN 80 4 mg/mL Sodium chloride 9
mg/mL Benzyl alcohol 9 mg/mL
The suspension is administered intramuscularly.
Hard Shell Capsules
[0539] A large number of unit capsules are prepared by filling
standard two-piece hard galantine capsules each with powdered
active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg
of magnesium stearate.
Soft Gelatin Capsules
[0540] A mixture of active ingredient in a digestible oil such as
soybean oil, cottonseed oil, or olive oil is prepared and injected
by means of a positive displacement pump into molten gelatin to
form soft gelatin capsules containing the active ingredient. The
capsules are washed and dried. The active ingredient can be
dissolved in a mixture of polyethylene glycol, glycerin and
sorbitol to prepare a water miscible medicine mix.
Immediate Release Tablets/Capsules
[0541] These are solid oral dosage forms made by conventional and
novel processes.
[0542] These units are taken orally without water for immediate
dissolution and delivery of the medication. The active ingredient
is mixed in a liquid containing ingredient such as sugar, gelatin,
pectin, and sweeteners. These liquids are solidified into solid
tablets or caplets by freeze drying and solid state extraction
techniques. The drug compounds may be compressed with viscoelastic
and thermoelastic sugars and polymers or effervescent components to
produce porous matrices intended for immediate release, without the
need of water.
[0543] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0544] While the invention has been illustrated with respect to the
production of particular compounds, it is readily apparent to those
of ordinary skill in the art that variations and modifications of
the invention can be made without departing from the spirit or
scope of the invention.
[0545] All publications and patents mentioned in the above
specification are incorporated herein by reference.
[0546] Various modifications and variations of the described
methods of the invention will be apparent to those skilled in the
art without departing from the scope and spirit of the invention.
Although the invention has been described in connection with
specific preferred embodiments, it should be understood that the
invention as claimed should not be unduly limited to such specific
embodiments. Indeed, various modifications of the above-described
modes for carrying out the invention which are obvious to those
skilled in the field of diabetes or related fields are intended to
be within the scope of the following claims. Those skilled in the
art will recognize, or be able to ascertain using no more than
routine experimentation, many equivalents to the specific
embodiments of the invention described herein. Such equivalents are
intended to be encompassed by the following claims.
* * * * *